DE60008372T2 - PHARMACEUTICAL ACTIVE COMPOUNDS - Google Patents

Description

The The present invention relates to novel compounds which are is protein kinase C inhibitors, process for their preparation, Intermediates for this and pharmaceutical compositions containing these compounds.

at Protein kinase C (PKC) is a family of phospholipid-dependent serine / threonine specifics Protein kinases that play an important role in controlling cell growth, play in cell regulation and cell differentiation.

There the activation of PKC in several human disease processes including various forms of cancer, various forms of inflammatory and / or immunological diseases as well as some neurological Diseases could be involved the inhibition of PKC in the treatment of these conditions therapeutic value.

It There are already several classes of compounds as PKC inhibitors been identified, for. B. Isochinolinsulfonamide, sphingosine and related sphingolipids, indolocarbazoles and bisindolylmaleinmides.

In the EP 0 328 026 describes the use of certain bisindolylmaleinmides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various conditions.

In Indian Journal of Heterocyclic Chemistry (1996), 269-272 Triazolylindole and Indolylthiazolidinone described.

Even though PKC inhibitors are described in the prior art Need for specific anti-inflammatory and immunosuppressive compounds for oral administration and are suitable for inhalation.

Of There is also a need for such compounds which are more soluble and less colored are, as the currently known PKC inhibitors.

object The present invention is kinase inhibitors in which it especially PKC inhibitors trade, process for their preparation and their preparation used intermediates.

The kinase inhibitors according to the invention are surprisingly better soluble and less colored as the kinase inhibitors known in the art, in particular PKC inhibitors.

object The present invention also relates to the use of the compounds according to the invention for the treatment of inflammatory Diseases, immunological diseases, bronchopulmonary diseases, cardiovascular Diseases, oncological diseases or degenerative CNS diseases.

object The present invention also relates to pharmaceutical compositions, containing a compound of the invention as an active ingredient together with a pharmaceutically acceptable adjunct, thinner or carrier.

worin einer der Reste Ar₁ und Ar₂ für gegebenenfalls substituiertes bicyclisches Heteroaryl oder gegebenenfalls substituiertes tricyclisches Heteroaryl und der andere für gegebenenfalls substituiertes Heteroaryl oder gegebenenfalls substituiertes Aryl steht;
X für O steht oder für den Fall, daß einer der Reste Ar₁ und Ar₂ für gegebenenfalls substituiertes bicyclisches Heteroaryl oder gegebenenfalls substituiertes tricyclisches Heteroaryl und der andere für gegebenenfalls substituiertes Heteroaryl steht, auch für S stehen kann und
R für H, OH, NH₂ oder C₁_₆-Alkyl (gegebenenfalls selbst substituiert durch Amino oder Hydroxy) steht;
Heteroaryl für Pyridinyl, Pyridin-2-onyl, Thienyl, Furyl, Pyrrolyl, Pyrazolyl, Chinolinyl, Isochinolinyl, Xanthen-9-yl, Chinolizin-3-yl, Benzothienyl, Benzofuryl, Indazolyl, 9H-Pyrido[3,4-b]indolyl, 1H-Pyrrolo[2,3-b]pyridinyl, 6,7,8,9-Tetrahydropyrido[1,2-a]indolyl, 2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl oder Indolyl steht und bicyclisches Heteroaryl und tricyclisches Heteroaryl entsprechend aus Heteroaryl ausgewählt sind;
Aryl für Phenyl oder Naphthyl steht;
der fakultative Substituent bzw. die fakultativen Substituenten an den Heteroaryl- und Arylgruppen aus der Gruppe bestehend aus Halogen, Cyano, Nitro, Hydroxy, CO₂(C₁_₄-Alkyl), C₁_₈-Alkyl (gegebenenfalls substituiert durch Halogen, Hydroxy, Cyano, C₁_₄-Alkoxy (gegebenenfalls substituiert durch NH₂, CO₂(C₁_₄-Alkyl)), NR^aR^b, SC (=NH) NH₂ , C(=NH)NR^cR^d, N=C(R^e)NR^fR^g, N(R^h)C(=O)Rⁱ, NHC(=NH)NH₁₂, Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder Phenyl-C_1–4-alkyl) , Phenyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino), C(=NH)OR^j, C(=NH)NR^kR^l), Pyridinyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino))), C_5–6-Cycloalkyl (gegebenenfalls substituiert durch Hydroxy, NR^mRⁿ oder Alkyl (gegebenenfalls selbst substituiert durch NR^oR^p)), C_5–6-Cycloalkenyl (gegebenenfalls substituiert durch NR^qR^r oder Alkyl (gegebenenfalls selbst substituiert durch NR^sR^t)), Heterocyclyl (gegebenenfalls substituiert durch C_l–4-Alkyl oder C_1–4-Halogenalkyl), Phenyl (gegebenenfalls substituiert durch Halogen), C_1–6-Alkoxy (gegebenenfalls substituiert durch Phenyl), Phenoxy und Amino (gegebenenfalls substituiert durch C_1–4-Alkyl) stammt bzw. stammen, wobei R^a, R^b, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^s und R^t unabhängig voneinander für Wasserstoff oder C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Hydroxy, Phenyl, CO₂H oder CO₂(C₁_₄-Alkyl)) stehen und R^c, R^d, R^e, R^f, R^g, R^h, Rⁱ, R^j, R^k und R¹ unabhängig voneinander für Wasserstoff, C_1–4-Alkyl oder Phenyl-C_1–4-alkyl stehen oder R^k und R¹ gemeinsam einen heterocyclischen Ring (wie Morpholin) bilden;
oder ein Salz oder Solvat davon oder ein Solvat eines Salzes davon;
mit der Maßgabe, daß für den Fall, daß X für O steht, R für Wasserstoff steht und einer der Reste Ar₁ und Ar₂ für Phenyl oder gegebenenfalls einfach durch Halogen oder C_1–4-Alkyl substituiertes Phenyl steht, der andere nicht für 3,4-Methylendioxyphenyl, unsubstituiertes Benzthiazol-2-yl, ein Phthalimid oder 1,8-Naphtalimid steht.The invention relates to a compound of the formula (I)

wherein one of Ar ₁ and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl;
X is O or in the event that one of the radicals Ar ₁ and Ar _{2 is} optionally substituted bicyclic Heteroaryl or optionally substituted tricyclic heteroaryl and the other represents optionally substituted heteroaryl, may also stand for S and
R is H, OH, NH ₂ or C ₁ _ ₆ alkyl (itself optionally substituted by amino or hydroxy) group;
Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl and bicyclic heteroaryl and tricyclic heteroaryl are respectively selected from heteroaryl;
Aryl is phenyl or naphthyl;
the optional substituent or the optional substituent on the heteroaryl and aryl groups selected from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C ₁ _ ₄ alkyl), C ₁ _ ₈ alkyl (optionally substituted by halogen, hydroxy, cyano, C ₁ _ ₄ alkoxy (optionally substituted by NH _2, CO ₂ (C ₁ _ ₄ alkyl)), NR ^a R ^b, SC (= NH) NH _2, C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₁₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino)), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (ge optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _l-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently represents hydrogen or C _1-4 alkyl (itself optionally substituted by hydroxy, phenyl, CO ₂ H or CO ₂ (C ₁ _ ₄ alkyl)), and R ^c, R ^d, R ^e, R ^f, R ^g , R ^h , R ⁱ , R ^j , R ^k and R ¹ independently represent hydrogen, C _1-4 alkyl or phenylC _1-4 alkyl or R ^k and R ¹ together form a heterocyclic ring (such as Morpholine);
or a salt or solvate thereof or a solvate of a salt thereof;
with the proviso that in the event that X is O, R is hydrogen and one of Ar ₁ and Ar _{2 is} phenyl or phenyl optionally substituted by halogen or C _1-4 alkyl, the other is not 3,4-methylenedioxyphenyl, unsubstituted benzthiazol-2-yl, a phthalimide or 1,8-naphthalimide.

In one aspect, the present invention provides a compound of formula (I) wherein Ar ₁ and Ar _{2 are} both bicyclic heteroaryl (wherein each heteroaryl has a single heteroatom, such as an N, O, or S atom) ,

In another embodiment, Ar ₁ and Ar ₂ are pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H Pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl, indolyl, benzothiophenyl, naphthyl and phenyl.

According to one Further embodiment, the present invention provides a compound of the formula (I) wherein heteroaryl and bicyclic heteroaryl are independently for substituted Indolyl, such as substituted indol-3-yl, for example with the substitution in 1 position, stand, ready.

According to one further embodiment X stands for Oxygen.

at the salts of the compounds of formula (I) are preferably to pharmaceutically acceptable salts. At the pharmaceutically acceptable Salts of compounds of the invention is It is preferably those that are good in the art are known to be suitable, and which are for example around acid addition salts (such as hydrochloride, hydrobromide or acetate salts) or a salt a compound of formula (I) with an alkyl halide (such as methyl bromide) is.

at Solvates of the compounds of the invention or salts are conveniently hydrates, such as Monohydrates or dihydrates.

Compounds of the invention shut down all stereoisomers and mixtures thereof in all proportions.

worin:
Ar₁ und Ar₂ für gegebenenfalls substituiertes Heteroaryl oder gegebenenfalls substituiertes Aryl stehen;
R für Wasserstoff oder C₁_₃-Alkyl steht;
X für 0 steht oder für den Fall, daß Ar₁ oder Ar₂ für gegebenenfalls substituiertes Heteroaryl steht, auch für S stehen kann;
Heteroaryl für Pyridinyl, Pyridin-2-onyl, Thienyl, Furyl, Pyrrolyl, Pyrazolyl, Chinolinyl, Isochinolinyl, Xanthen-9-yl, Chinolizin-3-yl, Benzothienyl, Benzofuryl, Indazolyl, 9H-Pyrido[3,4-b]indolyl, 1H-Pyrrolo[2,3-b]pyridinyl, 6,7,8,9-Tetrahydropyrido[1,2-a]indolyl, 2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl oder Indolyl steht;
Aryl für Phenyl oder Naphthyl steht;
der fakultative Substituent bzw. die fakultativen Substituenten an den Heteroaryl- und Arylgruppen aus der Gruppe bestehend aus Halogen, Cyano, Nitro, Hydroxy, CO₂ (C₁_₄-Alkyl) , C_1–8-Alkyl (gegebenenfalls substituiert durch Halogen, Hydroxy, Cyano, C₁_₄-Alkoxy (gegebenenfalls substituiert durch NH₂, CO₂ (C_1–4-Alkyl)), NR^aR^b, SC(=NH)NH₂, C(=NH)NR^cR^d, N=C(R^e)NR^fR^g, N(R^h)C(=O)Rⁱ, NHC(=NH)NH₂, Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder Phenyl-C_1–4-alkyl) , Phenyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino), C(=NH)OR^j, C(=NH)NR^kR^l), Pyridinyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino))), C_5–6-Cycloalkyl (gegebenenfalls substituiert durch Hydroxy, NR^mRⁿ oder Alkyl (gegebenenfalls selbst substituiert durch NR^oR^p)), C_5–6-Cycloalkenyl (gegebenenfalls substituiert durch NR^qR^r oder Alkyl (gegebenenfalls selbst substituiert durch NR^sR^t)), Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder C_1–4-Halogenalkyl), Phenyl (gegebenenfalls substituiert durch Halogen), C_1–6-Alkoxy (gegebenenfalls substituiert durch Phenyl), Phenoxy und Amino (gegebenenfalls substituiert durch C_1–4-Alkyl) stammt bzw. stammen, wobei R^a, R^b, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^s und R^t unabhängig voneinander für Wasserstoff oder C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Hydroxy, Phenyl, CO₂H oder CO₂ (C_1–4-Alkyl)) stehen und R^c, R^d, R^e, R^f, R^g, R^h, Rⁱ, R^j, R^k und R^l unabhängig voneinander für Wasserstoff, C_1–4-Alkyl oder Phenyl-C_1–4-alkyl stehen oder R^k und R¹ gemeinsam einen heterocyclischen Ring bilden;
R1 und R2 jeweils unabhängig voneinander für H, C_1–6-Alkyl, Halogen, C_1–3-Alkoxy, Benzyloxy, Hydroxy, Cyano, fluorsubsituiertes C_1–3-Alkyl, Carboxy oder Carbo-C_1–3-alkoxy stehen; R3 für H, C_1–6-Alkyl, Benzyl, C_1–3-alkoxysubsituiertes Benzyl, Hydroxy-C_1–6-alkyl, Hydroxy-C_3–7-cycloalkyl, Nitrilo-C_1–6-alkyl, Azido-C_1–6-alkyl, Amino-C_1–6-alkyl, Amino-C_3–6-cycloalkyl, Aminomethyl-C_3–7-cycloalkyl, Amino-C_5–7-cycloalkenyl, (Mono- oder Di-C_1–6-alkyl)amino-C_1–6-alkyl, Benzylamino-C_1–6-alkyl, (Mono- oder Di-C_1–6-alkyl amino-C_3–7-cycloalkyl, (Mono- oder Di- C_1–6-alkyl)aminomethyl-C_3–7-cycloalkyl, (Amino-C_1–3-alkylphenyl)-C_1–3-alkyl, Amino-C_1–3-alkylphenyl, Guanidino-C_1–6-alkyl, Amidino-C_1–6-alkyl, Amidinothio-C_1–6-alkyl, [N,N-Di-C_1–6-alkyl]amidino-C_1–6-alkyl, Amidino-C_1–3-alkylphenyl, [N,N-Mono- oder Di-C_1–6-alkyl]amidino-C_1–3-alkylphenyl, (N-Benzyl)amidino-C_1–3-alkylphenyl, (4-Morpholinyl)imino-C₁_₃-alkylphenyl, Benzimidsäuremethylester-C_1–3-alkyl, Hydroxy-C_1–3-alkylamino-C_1–6-alkyl, Carboxy-C_1–3-alkylamino-C_1–6-alkyl, Carboxymethyl-C_1–3-alkylamino-C_1–6-alkyl , Amino-C_1–3-alkyloxy-C_2–6-alkyl, Formamido-C_1–6-alkyl, (N,N-Dimethyl)imidoformamid-C_1–6-alkyl oder eine Gruppe der Formel -(CH2)n-Het, worin n eine ganze Zahl von 0–6 bedeutet und Het eine gegebenenfalls substituierte 5- oder 6-gliedrige heterocyclische Gruppe bedeutet, steht und R4 für H oder C₁_₃-Alkyl steht oder gemeinsam mit R3 einen anellierten Ring bildet, welcher gegebenenfalls durch Hydroxy-C_1–3-alkyl oder Amino-C_1–3-alkyl substituiert sein kann; oder ein Salz oder Solvat davon oder ein Solvat eines derartigen Salzes. Bevorzugt sind Verbindungen der Formel (II) und (III), worin Ar₁ oder Ar₂ für gegebenenfalls substituiertes bicyclisches Heteroaryl steht.The present invention according to yet a further embodiment of a compound of formula (II) or (III):

wherein:
Ar ₁ and Ar _{2 are} optionally substituted heteroaryl or optionally substituted aryl;
₃ -alkyl R is hydrogen or C ₁ _;
X is 0 or, in the case where Ar ₁ or Ar _{2 is} optionally substituted heteroaryl, may also stand for S;
Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl stands;
Aryl is phenyl or naphthyl;
the optional substituent or the optional substituent on the heteroaryl and aryl groups selected from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C ₁ _ ₄ alkyl), C _1-8 alkyl (optionally substituted by halogen, hydroxy, cyano, C ₁ _ ₄ alkoxy (optionally substituted by NH _2, CO ₂ (C _1-4 alkyl)), NR ^a R ^b, SC (= NH) NH _2, C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino)), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (gege optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another are hydrogen or C _1-4 -alkyl (optionally themselves substituted by hydroxyl, phenyl, CO ₂ H or CO ₂ (C _1-4 -alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , R ^j , R ^k and R ^l independently represent hydrogen, C _1-4 alkyl or phenylC _1-4 alkyl, or R ^k and R ¹ together form a heterocyclic ring;
R 1 and R 2 each independently represent H, C _1-6 alkyl, halogen, C _1-3 alkoxy, benzyloxy, hydroxy, cyano, fluoro-substituted C _1-3 alkyl, carboxy or carbo-C _1-3 alkoxy ; R 3 is H, C _1-6 -alkyl, benzyl, C _1-3 -alkoxy-substituted benzyl, hydroxy-C _1-6 -alkyl, hydroxy-C _3-7 -cycloalkyl, nitrilo-C _1-6 -alkyl, azido C _1-6 alkyl, amino C _1-6 alkyl, amino C _3-6 cycloalkyl, aminomethyl C _3-7 cycloalkyl, amino C _5-7 cycloalkenyl, (mono- or di-C _1-6- alkyl) amino-C _1-6 -alkyl, benzylamino-C _1-6 -alkyl, (mono- or di-C _1-6 -alkylamino-C _3-7 -cycloalkyl, (mono- or di C _1-6 alkyl) aminomethyl C _3-7 cycloalkyl, (amino C _1-3 alkylphenyl) C _1-3 alkyl, amino C _1-3 alkylphenyl, guanidino C _1-6 alkyl, amidinoC _1-6 alkyl, amidinothioC _1-6 alkyl, [N, N-diC _1-6 alkyl] amidinoC _1-6 alkyl, amidinoC _1-3 -alkylphenyl, [N, N-mono- or di-C _1-6 -alkyl] amidino-C _1-3 -alkylphenyl, (N-benzyl) amidino-C _1-3 -alkylphenyl, (4-morpholinyl) imino C ₁ _ ₃ alkylphenyl, Benzimidsäuremethylester-C _1-3 alkyl, hydroxy-C _1-3 -alkylamino-C _1-6 -alkyl, carboxy-C _1-3 alkylamino-C _1-6 alkyl, carboxymethyl 1-C _1-3 alkylaminoC _1-6 alkyl, aminoC _1-3 alkyloxyC _2-6 alkyl, formamidoC _1-6 alkyl, (N, N-dimethyl) imidoformamide C _{1 -6-} alkyl or a group of the formula - (CH2) n-Het, wherein n is an integer of 0-6 and Het represents represents an optionally substituted 5- or 6-membered heterocyclic group, and R 4 ₁ _ ₃ -alkyl H or C, or forms together with R3 a fused ring which is optionally substituted by Hydroxy C _1-3 alkyl or amino C _1-3 alkyl; or a salt or solvate thereof or a solvate of such a salt. Preference is given to compounds of the formula (II) and (III) in which Ar ₁ or Ar _{2 represents} optionally substituted bicyclic heteroaryl.

worin R, R1, R2, R3 und R4 die in Anspruch 5 angegebene Bedeutung besitzen und Ar₂ für gegebenenfalls substituiertes bicyclisches Heteroaryl oder gegebenenfalls substituiertes tricyclisches Heteroaryl steht;
bicyclisches Heteroaryl und tricyclisches Heteroaryl entsprechend unter Chinolinyl, Isochinolinyl, Xanthen-9-yl, Chinolizin-3-yl, Benzothienyl, Benzofuryl, Indazolyl, 9H-Pyrido[3,4-b]indolyl, 1H-Pyrrolo[2,3-b]pyridinyl, 6,7,8,9-Tetrahydropyrido[1,2-a]indolyl, 2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl oder Indolyl ausgewählt sind;
bicyclisches Heteroaryl und tricyclisches Heteroaryl gegebenenfalls durch Halogen, Cyano, Nitro, Hydroxy, CO₂ (C_1–4-Alkyl), C_1–8-Alkyl (gegebenenfalls substituiert durch Halogen, Hydroxy, Cyano, C₁_₄-Alkoxy (gegebenenfalls substituiert durch NH₂, CO₂(C₁_₄-Alkyl)), NR^aR^b, SC(=NH)NH₂, C(=NH)NR^cR^d, N=C(R^e) NR^fR^g, N(R^h)C(=O)Rⁱ, NHC(=NH)NH₂, Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder Phenyl-C_1–4-alkyl) , Phenyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino), C(=NH)OR^j, C(=NH)NR^kR^l), Pyridinyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino))), C_5–6-Cycloalkyl (gegebenenfalls substituiert durch Hydroxy, NR^mRⁿ oder Alkyl (gegebenenfalls selbst substituiert durch NR^oR^p)), C_5–6-Cycloalkenyl (gegebenenfalls substituiert durch NR^qR^r oder Alkyl (gegebenenfalls selbst substituiert durch NR^sR^t)), Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder C_1–4-Halogenalkyl) , Phenyl (gegebenenfalls substituiert durch Halogen), C_1–6-Alkoxy (gegebenenfalls substituiert durch Phenyl), Phenoxy und Amino (gegebenenfalls substituiert durch C_1–4-Alkyl) substituiert sind, wobei R^a, R^b, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^s und R^t unabhängig voneinander für Wasserstoff oder C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Hydroxy, Phenyl, CO₂H oder CO₂(C₁_₄-Alkyl)) stehen und R^c, R^d, R^e, R^f, R^g, R^h, Rⁱ, R^j, R^k und R^l unabhängig voneinander für Wasserstoff, C_1–4-Alkyl oder Phenyl-C_1–4-alkyl stehen oder R^k und R¹ gemeinsam einen heterocyclischen Ring bilden.The present invention, according to a further embodiment, a compound of formula (XV):

wherein R, R 1, R _2, R 3 and R _{4 are} as defined in claim 5 and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl;
bicyclic heteroaryl and tricyclic heteroaryl corresponding to quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b ] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or indolyl;
bicyclic heteroaryl and tricyclic heteroaryl are optionally substituted by halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 alkyl (optionally substituted by halogen, hydroxy, cyano, C ₁ _ ₄ alkoxy (optionally ^b substituted by NH _2, CO ₂ (C ₁ _ ₄ alkyl)), NR ^a R, SC (= NH) NH _2, C (= NH) NR ^c R ^d, N = C (R ^e) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenylC _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally substituted by amino itself )), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (optionally self-substituted by NR ^s R ^t )), Hete rocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl), phenoxy and amino (optionally substituted by C _{1 4-} alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another represent hydrogen or C _1-4 -alkyl ( itself optionally substituted by hydroxy, phenyl, CO ₂ H or CO ₂ (C ₁ _ ₄ alkyl)), and R ^c, R ^d, R ^e, R ^f, R ^g, R ^h, R ^i, R ^j, R ^k and R ^l independently of one another are hydrogen, C _1-4 -alkyl or phenyl-C _1-4 -alkyl or R ^k and R ¹ together form a heterocyclic ring.

worin R1 bis R4 die in Formel (II) und Formel (III) angegebene Bedeutung besitzen, R5 für H, C₁_₆-Alkyl, Benzyl, Hydroxy-C_1–6-alkyl oder Amino-C_1–6-alkyl steht und R6 und R7 unabhängig voneinander für H, C_1–3-Alkyl, Halogen, fluorsubsituiertes C_1–3-Alkyl, C_1–3-Alkoxy, Benzyloxy, Hydroxy, Cyano, Carboxy oder Carbo-C₁_₃-alkoxy stehen; oder ein Salz oder Solvat davon oder ein Solvat eines derartigen Salzes.The present invention is according to yet another embodiment, a compound of formula (IV)

wherein R _{1 to} R _{4 are as} defined in formula (II) and formula (III), R 5 is H, C _1-6 alkyl, benzyl, hydroxyC _1-6 alkyl or aminoC _1-6 alkyl and R6 and R7 independently represent H, C _1-3 alkyl, halogen, fluoro-substituted C _1-3 alkyl, C _1-3 alkoxy, benzyloxy, hydroxy, cyano, carboxy or carbo-C ₁ _ ₃ alkoxy ; or a salt or solvate thereof or a solvate of such a salt.

For compounds of formula (IV), the following independent preferences apply: R3 or R5 is aminopropyl, aminobutyl, aminopentyl, aminocyclopentyl, aminomethylcyclopentyl, (dimethylamino) methylcyclopenthyl, guanidinopropyl, amidinopropyl, amidinobutyl, amidinothiopropyl, ethylaminopropyl, dimethylaminopropyl, dimethylaminobutyl, morpholinopropyl, methylpiperazinopropyl Methylpiperidinyl, piperidinomethyl, benzylpiperidinomethyl, diethylaminocyclopentyl or dimethylaminocyclopentyl;
R1, R2, R6 and R7 are each independently methyl, methoxy, cyano or halogen, preferably F or C1.

In still further preferred embodiments of formula (I) Ar ₁ and / or Ar _{2 are selected} from benzothiophene, naphthyl, optionally substituted phenyl and optionally substituted indolyl. Optional substituents for Ar ₁ and / or Ar ₂ include aminopropyl, aminobutyl, ethylaminopropyl, ethylaminobutyl, dimethylaminopropyl, dimethylaminobutyl, aminocyclopentyl, ethylaminocyclopentyl, dimethylaminocyclopentyl, amidinoalkyl, amidinothioalkyl and guanidinoalkyl.

worin:
Ar die oben für Ar₁ und Ar₂ angegebene Bedeutung besitzt;
R für Wasserstoff oder C_1–3-Alkyl steht;
R1 und R2 jeweils unabhängig voneinander für H, C_1–6-Alkyl, Halogen, C_1–3-Alkoxy, Benzyloxy, Hydroxy, Carboxy, Carbo-C_1–3-Alkoxy, Carbamoyl und C_1–3-Alkylcarbamoyl stehen;
R3 für H, C_1–6-Alkyl, Benzyl, C_1–3-alkoxysubstituiertes Benzyl, Hydroxy-C_1–6-alkyl, Hydroxy-C_3–7-cycloalkyl, Nitrilo-C_1–6-alkyl, Azido-C_1–6-alkyl, Amino-C_1–6-alkyl, Amino-C_3–7-cycloalkyl, (Mono- oder Di-C_1–6-alkyl)amino-C_1–6-alkyl, (Mono- oder Di-C_1–6-alkyl)amino-C_3–7-cycloalkyl, (Amino-C_1–3-alkylphenyl)-C_1–3-alkyl, Amino-C_1–3-alkylphenyl, Guanidino-C_1–6-alkyl, amidino-C_1–6-Alkyl, amidinothio-C_1–6-alkyl, Amino-C_1–6-alkoxy substituiertes Alkyl, amino-C_1–6-hydroxysubstituiertes Alkyl, amino-C_1–6-aminosubstituiertes Alkyl oder eine Gruppe der Formel -(CH₂)_n-Het, worin
n eine ganze Zahl von 1–6 bedeutet und
Het eine gegebenenfalls substituierte 5- oder 6-gliedrige heterocyclische Gruppe bedeutet, steht und
R4 für H oder C_1–3-Alkyl steht oder gemeinsam mit R3 einen anellierten Ring bildet, welcher gegebenenfalls durch Hydroxy-C_1–3-alkyl oder Amino-C_1–3-alkyl substituiert sein kann,
sowie Salze und Solvate davon und Solvate derartiger Salze.Preferred embodiments of the formula (I) are compounds of the formula (II) and (III)

wherein:
Ar has the meaning given above for Ar ₁ and Ar ₂ ;
R is hydrogen or C _1-3 alkyl;
R 1 and R 2 are each independently H, C _1-6 alkyl, halo, C _1-3 alkoxy, benzyloxy, hydroxy, carboxy, carbo-C _1-3 alkoxy, carbamoyl and C _1-3 alkylcarbamoyl;
R 3 is H, C _1-6 -alkyl, benzyl, C _1-3 -alkoxy-substituted benzyl, hydroxy-C _1-6 -alkyl, hydroxy-C _3-7 -cycloalkyl, nitrilo-C _1-6 -alkyl, azido C _1-6 -alkyl, amino-C _1-6 -alkyl, amino-C _3-7 -cycloalkyl, (mono- or di-C _1-6 -alkyl) -amino-C _1-6 -alkyl, (mono-C _1-6 -alkyl) or di-C _1-6 -alkyl) amino-C _3-7 -cycloalkyl, (amino-C _1-3 -alkylphenyl) C _1-3 -alkyl, amino-C _1-3 -alkylphenyl, guanidino-C _{1 -6} alkyl, amidino-C _1-6 alkyl, amidinothio C _1-6 alkyl, amino-C _1-6 -alkoxy-substituted alkyl, amino-C _1-6 -hydroxysubstituiertes alkyl, amino-C _1-6 -amino-substituted alkyl or a group of the formula - (CH ₂ ) _n -Het, wherein
n means an integer of 1-6 and
Het is an optionally substituted 5- or 6-membered heterocyclic group, and
R 4 is H or C _1-3 -alkyl or together with R 3 forms a fused ring which may optionally be substituted by hydroxyC _1-3 -alkyl or aminoC _1-3 -alkyl,
and salts and solvates thereof and solvates of such salts.

Especially preferred embodiments of the formula (I) are compounds of the formula (II) and (III) wherein Ar for an optionally substituted bicyclic heteroaromatic Group stands.

worin
R1–R4 die unter Formel (II) und (III) angegebene Bedeutung besitzen,
R5 für H, C_1–6-Alkyl, Benzyl, Hydroxy-C_1–6-alkyl oder Amino-C_1–6-alkyl steht und
R6 und R7 unabhängig voneinander für H, C_1–3-Alkyl, Halogen, C_1–3-Alkoxy, Benzyloxy, Hydroxy, Carboxy, Carbo-C_1–3-alkoxy, Carbamoyl und C_1–3-Alkylcarbamoyl stehen, sowie Salze und Solvate davon und Solvate derartiger Salze.Even more preferred embodiments of the formula (I) are compounds of the formula (IV)

wherein
R1-R4 have the meaning given under formulas (II) and (III),
R5 is H, C _1-6 alkyl, benzyl, hydroxyC _1-6 alkyl or aminoC _1-6 alkyl and
R6 and R7 are independently H, C _1-3 alkyl, halo, C _1-3 alkoxy, benzyloxy, hydroxy, carboxy, carbo-C _1-3 alkoxy, carbamoyl and C _1-3 alkylcarbamoyl, and Salts and solvates thereof and solvates of such salts.

For compounds of formula (IV), the following independent preferences apply:
-R3 or R5 is aminoethyl, aminopropyl, aminobutyl, aminomethyl, benzyl, aminocyclopentyl, guanidinopropyl, amidinobutyl, amidinothiopropyl, ethylaminopropyl, ethylaminobutyl, dimethylaminopropyl, dime thylaminobutyl, ethylaminocyclopentyl or dimethylaminocyclopentyl.
Each of R1, R2, R6 and R7 is independently halogen, preferably F or Cl.

Preferred compounds of the invention include:
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methyl-indol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one,
4- [1- (4-aminobutyl) -5-fluoroindole-3-yl] -5- (5-fluoro-1-methyl-indol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one,
4- [1- (5-aminopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methyl-indol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one,
4- [1- (3-dimethylaminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazole 3-one,
4- [1- (3-dimethylaminobutyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazole 3-one, 4- [1- (3-ethylaminopropyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2, 4] triazol-3-one,
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one,
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1H-indol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one,
5- (5-fluoro-1-methylindol-3-yl] -4- [5-fluoro-1- (3-morpholin-4-yl-propyl) -indole-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one,
5- (5-fluoro-1-methylindol-3-yl] -4- {5-fluoro-1- [3- (4-methylpiperazin-1-yl) propyl] indol-3-yl} -2,4 dihydro [1,2,4] triazol-3-one,
2- (3- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4- yl] -indole-1-yl} -propyl) isothiourea,
N- (3- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4- yl] -indole-1-yl} -propyl) guanidine,
5- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] - indol-1-yl} -butanamidin,
5- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] - indol-1-yl} -pentanamidin,
4- [1 (S) - (3 (S) -Aminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
4- [1 (R) - (3 (R) -Aminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one,
4- [1 (S) - (3 (R) -Aminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one,
4- [1 (R) - (3 (S) -Aminocyclopentyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
4- [1 (S) - (3 (S) -Aminocyclopentyl) indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one,
4- [1 (S) - (3 (S) -Dimethylaminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one,
4- [1 (S) - (3 (S) -Diethylaminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
4- [1 (S) - (3 (R) -Aminomethylcyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
4- [1 (S) - (3 (R) -Dimethylaminomethylcyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
5- (5-fluoro-1-methylindol-3-yl) -4- (5-fluoro-1-piperidin-4-ylmethylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one,
5- (5-fluoro-1-methylindol-3-yl) -4- (5-fluoro-1- (1-methylpiperidin-4-yl) indol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
4- [1- (1-Benzyl-4-ylmethyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2 , 4] triazol-3-one,
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1,5-dimethylindole-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-chloro-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one,
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-cyano-1-
methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one,
4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-methoxy-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one,
4- [1- (3-aminopropyl) -5-chloroindole-3-yl] -5- (5-chloro-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one,
4- (1-methylindole-3-yl) -5- (8-aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one,
or a salt or a solvate thereof or a solvate of such a salt.

manufacturing the compounds of the invention

• (a) Verbindungen der Formel (I), worin R für C_1–3-Alkyl (gegebenenfalls substituiert durch Amino oder Hydroxy) steht, bei dem man eine Verbindung der Formel (I), in der R für Wasserstoff steht, mit dem entsprechenden (gegebenenfalls durch Amino oder Hydroxy substituierten) C_1–3-Alkyl-Alkylierungsmittel alkyliert.
• (b) Zur Synthese von Verbindungen der Formel (I), in der R für H steht, kann man eine Verbindung der Formel (VI):
  
  worin Ar₁ und Ar₂ die unter Formel (I) angegebene Bedeutung besitzen, intramolekular kondensieren.
• (c) Zur Synthese von Verbindungen der Formel (I) kann man eine Verbindung der Formel (I) in ein Salz und insbesondere ein pharmazeutisch unbedenkliches Salz davon umwandeln, oder umgekehrt, oder ein Salz und insbesondere ein pharmazeutisch unbedenkliches Salz einer Verbindung der Formel (I) in ein anderes Salz und insbesondere ein pharmazeutisch unbedenkliches Salz umwandeln.

Compounds of formula (I) can be synthesized as follows:

• (a) Compounds of formula (I) wherein R is C _1-3 alkyl (optionally substituted by amino or hydroxy) which comprises reacting a compound of formula (I) wherein R is hydrogen with the corresponding one (optionally substituted by amino or hydroxy) alkyl C _1-3 alkylating agent.
• (b) For the synthesis of compounds of the formula (I) in which R is H, a compound of the formula (VI):
  
  wherein Ar ₁ and Ar _{2 have} the meaning given under formula (I), intramolecular condensation.
• (c) For the synthesis of compounds of the formula (I), a compound of the formula (I) can be converted into a salt and especially a pharmaceutically acceptable salt thereof, or vice versa, or a salt and in particular a pharmaceutically acceptable salt of a compound of the formula ( I) into another salt and in particular a pharmaceutically acceptable salt.

The Condensation may suitably in the presence of trimethylsilyl triflate or bistrimethylsilylacetamide and a base, e.g. As triethylamine, in dimethylformamide at Temperature in the range of about 100 ° C to 160 ° C, preferably from 115 ° C to 145 ° C and preferably at about 130 ° C, over a period of time in the range of about 5 minutes to about 6 hours, suitably from 15 minutes to 3 hours and preferably about 1 hour.

For the preparation of a compound of the formula (I) in which Ar ₁ , Ar ₂ and / or R carry one or more functional groups which may be sensitive to or disturb the reaction conditions in the processes in (a) or (b), It is possible to use a corresponding starting material in which the functional group or functional groups are or are suitably protected and then deprotect according to the process of (a) or (b).

functional Groups facing each other the reaction conditions in the method (a) or (b) sensitive be or disturb this can, as well as suitable protecting groups and deprotection methods are apparent to those skilled in the art obviously.

The Starting materials for the above processes (a), (b) and (c) can be carried out according to the methods described herein Process and in particular according to those described in the examples Process or be prepared in analogy. Other conventional Methods for preparing the starting materials are obvious to the person skilled in the art.

to Preparation of a compound of formula (II) or (III) or a Salt thereof, wherein at least one of the substituents R3 or Ar carries an amino or hydroxyl group, you can the corresponding A compound of the formula (II) and (III) in which the amino or hydroxyl group protected is deprotect.

at The above-described methods are the protecting groups and the Conditions for the deprotection Professional well known. Suitable protecting groups for amino groups are, for. For example, t-butoxycarbonyl groups, and as a deprotecting agent you can use trifluoroacetic acid in a suitable solvent, z. As a mixture of acetonitrile and water use. The hydroxyl groups can as their corresponding tert-butyldimethylsilyloxy groups Protected (TBDMS-oxy groups) and as a deprotection agent you can get acetic acid in z. For example, use water. The deprotection can be done in a suitable Solvent, z. For example, tetrahydrofuran, at about 60-80 ° C, z. B. over a period of about 2 hours, performed become.

A comprehensive description of the use of protecting groups yourself "Protective Groups in Organic Chemistry ", Publisher J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis ", 2nd Edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991).

worin R, R1, R2, R4 und Ar die unter Formel (II) und (III) angegebene Bedeutung besitzen und R3₁₁ für eine Alkylgruppe steht, reduzieren.For the preparation of compounds of the formula (II) or (III) in which R 3 is an amino-bearing alkyl group, a compound of the formula (IX) or (X) can be prepared.

wherein R, R1, R2, R4 and Ar have the meaning given under formula (II) and (III) and R3 _{11 is} an alkyl group reduce.

at In the above process, the conditions for the reduction are those skilled in the art well known. Suitable conditions for the reduction of the azido group are z. B. hydrogenation at Pd / C at atmospheric pressure or the application of Staudinger conditions, d. H. Triphenylphosphine in pyridine with followed by Addition of aqueous ammonia.

worin R, R1, R2, R4 und Ar die unter Formel (II) und (III) angegebene Bedeutung besitzen und R3₁₁ für eine Alkylgruppe steht und LG für eine Abgangsgruppe, z. B. Mesylat oder Bromid, steht, umsetzen.For the preparation of compounds of the formula (II) or (III) in which R 3 is a thioamidino, monoalkylamino, dialkylamino or trialkylamino-bearing alkyl group, a compound of the formula (XI) or (XII) with thiourea or a suitable monoalkyl, dialkyl or trialkylamine:

wherein R, R1, R2, R4 and Ar have the meaning given under formula (II) and (III) and R3 _{11 is} an alkyl group and LG is a leaving group, for. As mesylate or bromide, react.

worin R, R1, R2, R4 und Ar die unter Formel (II) und (III) angegebene Bedeutung besitzen und R3₁₁ für eine Alkylgruppe steht, transformieren.For the synthesis of compounds of the formula (XI) and (XII), the alcohol function in compounds of the formula (XIII) and (XIV) can be determined under standard conditions which are well known to the person skilled in the art:

wherein R, R1, R2, R4 and Ar have the meaning given under formula (II) and (III) and R3 _{11 is} an alkyl group, transform.

For the synthesis of compounds of the formula (II) in which R 3 is an alkyl or phenylalkyl group carrying an amidino or guanidino group, compounds of the formula (XV) which correspond to the formula (II) but in which R 3 is a Nitrile- or primary amino-bearing alkyl group is, with hydrogen chloride in ethanol and then with ammonia in methanol or in refluxing ethanol and in the presence a base with 3,5-dimethylpyrazole-1-carboxamidiniumnitrat implement.

to Preparation of compounds of the formula (II) or (III) according to the above Definition wherein R3 is for is an alkyl group carrying an amidino or guanidino group, can be: (i) a compound of formula (II) or (III), wherein R3 for a nitrile group bearing alkyl group, with hydrogen chloride in ethanol and then with ammonia in methanol or (ii) a compound of formula (II) or (III) wherein R3 is a primary Amino group bearing alkyl group, in refluxing ethanol in the presence of a base with 3,5-dimethylpyrazole-1-carboxamidinium nitrate implement.

to Preparation of compounds of the formula (II) or (III) according to the above Definition wherein R3 is for an N-substituted or N, N-disubstituted amidino group carrying alkyl or phenylalkyl group, you can use a compound of the formula (II) or (III) wherein R 3 represents a nitrile group-bearing one Alkyl or phenylalkyl group, with hydrogen chloride in methanol and then react with the appropriate amine in methanol.

As for the One skilled in the art can be easily seen, one can for the preparation of compounds of the invention in an alternative and sometimes more convenient manner, the above listed individual Perform process steps in a different order and / or the individual reactions in another stage of the overall route carry out. This depends z. Of factors such as the nature of others, in a given Substrate present functional groups, availability of key intermediates and of the applicable protection group strategy.

New Intermediates according to the above Description and its use in the production of others Compounds of the invention are also part of the invention. The subject of the invention is thus according to a further embodiment of an intermediate compound of the formula (VI), (IX), (X), (XI), (XII), (XIII) or (XIV) as defined above.

prodrugs

For the expert Furthermore, it is readily apparent that certain protected derivatives of compounds of formula (I), (II), (III), (IV) and (XV), which before a final deprotection can be produced maybe in itself are not pharmacologically active, but after parenteral or oral Administration in the body to form pharmacologically effective Verbindun gene according to the invention can be metabolized. Such derivatives can therefore be described as "prodrugs". In addition, certain Compounds of formula (I), (II), (III), (IV) and (XV) as prodrugs for others Compounds of formula (I), (II), (III), (IV) and (XV) function.

medical and pharmaceutical use

object The present invention also relates to compounds of the invention for use in medical therapy; the use of a compound of the invention in the manufacture of medicaments for use in the treatment the states described here as well as methods of medical therapy involving one Person in need of such a therapy, a therapeutically effective Amount of a compound of the invention administered.

in the In the context of the present invention, the term "medical therapy" is intended to be prophylactic, include diagnostic and therapeutic regimens that in vivo or ex vivo to humans or other mammals.

The Compounds of formula (I), (II), (III), (IV) and (XV) and pharmaceutically acceptable salts thereof are useful because they show pharmacological action. In particular, they show Effect as kinase inhibitors, in particular PKC inhibitors, such as z. B. their effect in the in M.J. Jirousek et al., J. Med. Chem. 1996, 39, 2664-2571, R.A. Granet et. al., analyte. Biochem. 1987, 163, 458-463; H. Olsson et. al., Cell Signal 1989, 1, 405-410; and B.R. Chakravarthy et. al., analyte. Biochem. 1991, 196, 144-150, described in vitro assays shows.

The compounds of the invention are indicated for use in the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or degenerative CNS disorders; preferably for oral or topical treatment of inflammatory and / or immunological diseases, such. B. the ora le or topical treatment of respiratory diseases with inflammatory conditions, e.g. Asthma, chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema; or atopic diseases, e.g. Rhinitis or atopic dermatitis; inflammatory bowel disease, z. Crohn's disease or colitis; Autoimmune diseases, e.g. Multiple sclerosis, diabetes, atherosclerosis, psoriasis, systemic lupus erythematosus or rheumatoid arthritis; malignant diseases, e.g. Skin or lung cancer; HIV infections or AIDS; or to inhibit rejection of organs / transplants. The compounds of the invention are also indicated for use in the treatment of heart failure and in the treatment of diabetic patients with macular edema or diabetic retinopathy.

worin einer der Reste Ar₁ und Ar₂ für gegebenenfalls substituiertes bicyclisches Heteroaryl oder gegebenenfalls substituiertes tricyclisches Heteroaryl und der andere für gegebenenfalls substituiertes Heteroaryl oder gegebenenfalls substituiertes Aryl steht;
X für O oder S steht und
R für H, OH, NH₂ oder C_1–6-Alkyl (gegebenenfalls selbst substituiert durch Amino oder Hydroxy) steht;
Heteroaryl für Pyridinyl, Pyridin-2-onyl, Thienyl, Furyl, Pyrrolyl, Pyrazolyl, Chinolinyl, Isochinolinyl, Xanthen-9-yl, Chinolizin-3-yl, Benzothienyl, Benzofuryl, Indazolyl, 9H-Pyrido[3,4-b]indolyl, 1H-Pyrrolo[2,3-b]pyridinyl, 6,7,8,9-Tetrahydropyrido[1,2-a]indolyl, 2,3-Dihydro-1H-pyrrolo[1,2-a]indolyl oder Indolyl steht und bicyclisches Heteroaryl und tricyclisches Heteroaryl entsprechend aus Heteroaryl ausgewählt sind;
Aryl für Phenyl oder Naphthyl steht;
der fakultative Substituent bzw. die fakultativen Substituenten an den Heteroaryl- und Arylgruppen aus der Gruppe bestehend aus Halogen, Cyano, Nitro, Hydroxy, CO₂(C_1–4-Alkyl), C_1–8-Alkyl (gegebenenfalls substituiert durch Halogen, Hydroxy, Cyano, C₁–₄-Alkoxy (gegebenenfalls substituiert durch NH₂, CO₂(C_1–4-Alkyl)), NR^aR^b , SC(=NH)NH₂ , C(=NH)NR^cR^d , N=C(R^e)NR^fR^g, N(R^h)C(=O)Rⁱ, NHC(=NH)NH₂, Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder Phenyl-C_1–4-alkyl), Phenyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino), C(=NH)OR^j, C(=NH)NR^kR^l), Pyridinyl (gegebenenfalls substituiert durch C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Amino))), C_5–6-Cycloalkyl (gegebenenfalls substituiert durch Hydroxy, NR^mRⁿ oder Alkyl (gegebenenfalls selbst substituiert durch NR^oR^p)), C^5–6-Cycloalkenyl (gegebenenfalls substituiert durch NR^qR^r oder Alkyl (gegebenenfalls selbst substituiert durch NR^sR^t)), Heterocyclyl (gegebenenfalls substituiert durch C_1–4-Alkyl oder C_1–4-Halogenalkyl) , Phenyl (gegebenenfalls substituiert durch Halogen), C_1–6-Alkoxy (gegebenenfalls substituiert durch Phenyl), Phenoxy und Amino (gegebenenfalls substituiert durch C_1–4-Alkyl) stammt bzw. stammen, wobei R^a, R^b, R^m, Rⁿ, R^o, R^p, R^q, R^r, R^s und R^t unabhängig voneinander für Wasserstoff oder C_1–4-Alkyl (gegebenenfalls selbst substituiert durch Hydroxy, Phenyl, CO₂H oder CO₂( C_1–4-Alkyl)) stehen und R^c, R^d, R^e, R^f, R^g, R^h, Rⁱ, R^j, R^k und R^l unabhängig voneinander für Wasserstoff, C₁–₄-Alkyl oder Phenyl-C_1–4-alkyl stehen oder R^k und R^l gemeinsam einen heterocyclischen Ring bilden;
oder eines Salzes, Solvats oder Hydrats davon oder eines Solvats oder Hydrats eines Salzes davon bei der Herstellung eines Arzneimittels zur Verwendung bei entzündlichen Erkrankungen, immunologischen Erkrankungen, bronchopulmonalen Erkrankungen, kardiovaskulären Erkrankungen, onkologischen Erkrankungen oder ZNS-Erkrankungen.The present invention is thus in a further embodiment, the use of a compound of formula (I):

wherein one of Ar ₁ and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl;
X stands for O or S and
R is H, OH, NH ₂ or C _1-6 alkyl (optionally self-substituted by amino or hydroxy);
Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl and bicyclic heteroaryl and tricyclic heteroaryl are respectively selected from heteroaryl;
Aryl is phenyl or naphthyl;
the optional substituent or the optional substituents on the heteroaryl and aryl groups from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 -alkyl (optionally substituted by halogen, hydroxy, cyano, C _1-4 alkoxy (optionally substituted by NH _2, CO ₂ (C _1-4 alkyl)), NR ^a R ^b, SC (= NH) NH _2, C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino)), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C ^5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (gege optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another are hydrogen or C _1-4 -alkyl (optionally themselves substituted by hydroxyl, phenyl, CO ₂ H or CO ₂ (C _1-4 -alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^g, R ^h, R ^i, R ^j, R ^k and R ^l are each independently hydrogen, C _1-4 alkyl or phenyl-C _1-4 alkyl, or are R ^k and R ^l together form a heterocyclic ring;
or a salt, solvate or hydrate thereof or a solvate or hydrate of a salt thereof in the manufacture of a medicament for use in inflammatory diseases, immunological diseases, bronchopulmonary diseases, cardiovascular diseases, oncological diseases or CNS diseases.

pharmaceutical preparations

The in each case to be administered dose of the compound is of the respective Indication and age, weight and gender of the patient depend and can be determined by a doctor. The dosage is preferably range from 0.01 mg / kg to 10 mg / kg.

The compounds may be topically, e.g. To the lungs and / or the respiratory tract, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, e.g. B. formulations in known by the name Turbuhaler ^® inhaler device; or systemically, e.g. By oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration, z. In the form of sterile parenteral solutions or suspensions, or by rectal administration, e.g. In the form of suppositories.

The Compounds of the invention can for themselves alone or in the form of a pharmaceutical composition which the compound of the invention in combination with a pharmaceutically acceptable diluent, Excipient and / or carrier contains be administered. Particular preference is given to compositions without Substances that have an adverse, z. An allergic reaction can cause.

Dry powder formulations and HFA pressure aerosols of the compounds of the invention can be administered by oral or nasal inhalation. For inhalation, the compound is desirably in finely divided form. The finely divided compound preferably has a mass-average diameter of less than 10 microns and can with the aid of a dispersant, such as. A C ₈ -C ₂₀ fatty acid or a salt thereof (e.g., oleic acid), a gallium salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant or other pharmaceutically acceptable dispersant, in a propellant mixture.

The Compounds of the invention can also be administered with the aid of a dry powder inhaler. The inhaler may be a single dose or multiple dose inhaler and a breath-activated dry powder inhaler.

A possibility is the finely divided compound with a carrier, z. B. a mono-, di- or polysaccharide, a sugar alcohol or another polyol, to mix. Suitable carriers are sugars, for. Lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, Sucrose, mannitol and starch. Alternatively, one can have the finely divided compound with another Coat substance. You can also fill the powder mixture in hard gelatin capsules, the each the desired Drug dose included.

Another possibility is to process the finely divided powder into beads which disintegrate upon inhalation. This spheronised powder may be added to the drug reservoir of a multi-dose inhaler, e.g. B. the known by the name Turbuhaler ^® inhaler in which a dosing unit meters the desired dose which is then inhaled by the patient fill. With this system, the drug with or without carrier substance is supplied to the patient.

to Oral administration can be the active ingredient with an excipient or carrier, z. Lactose, sucrose, sorbitol, mannitol; a strength, for. Potato starch, corn starch or amylopectin; a cellulose derivative; a binder, e.g. Gelatin or polyvinylpyrrolidone, and / or a lubricant, z. As magnesium stearate, calcium stearate, polyethylene glycol, a Wax, a paraffin and the like, and then mix into tablets compress. If coated tablets are desired, you can use the like Kernels prepared above with a concentrated sugar solution, the z. Gum arabic, gelatin, talc, titanium dioxide and the like may contain. Alternatively, you can use the tablet with a suitable, in one volatile organic solvents dissolved Coat polymer.

to Production of soft gelatin capsules can be the compound z. B. with a vegetable oil or polyethylene glycol. Hard gelatin capsules can Containing granules of the compound, wherein one of the above-listed tablet carriers is used. Furthermore can you liquid or semi-solid formulations of the drug in hard gelatin capsules to fill.

Liquid preparations for oral administration in the form of syrups or suspensions, for example as solutions, the compound and the remainder sugar and a mixture of ethanol, water, Glycerol and propylene glycol. Such liquid preparations can optionally colorants, flavoring agents, saccharin and / or Carboxymethylcellulose as thickener or other, known in the art Excipients included.

The Compounds of the invention can Also in conjunction with other compounds for treatment the above states be administered.

The Invention will now be explained with reference to the following examples, but be restricted in any way.

All reactions were carried out in dried glassware in argon or nitrogen atmosphere at room temperature unless otherwise stated. Tetrahydrofuran (THF) was distilled over sodium benzophenone ketyl prior to use. N, N-dimethylformamide (DMF) was distilled over calcium hydride and stored over molecular sieves. All other solvents and reagents were used as supplied.

¹ H NMR spectra were recorded on a Varian Inova 400 or Unity 500 + instrument. Here, the central solvent peak of chloroform-d (δ _H 7.27 ppm), dimethyl sulfoxide-d ₆ (δ _H 2.50 ppm) or methanol-d ₄ (δ _H 3.35 ppm) served as an internal reference. Low resolution mass spectra were recorded on a Fisons Analytical Autospek-Q double focus focusing field instrument with a LSIMS interface. Low-resolution mass spectra were also obtained on a Hewlett Packard 1100 LC-MS system with an APCI ionization chamber.

The Analytical HPLC was performed on a Hewlett LC-MS 1100 instrument Packard with a C-18 reverse phase column and carried out using the following general system as eluent: acetonitrile / water (Gradient from 20:80 to 90:10) with 0.1% TFA.

The preparative LC was run on a Kromasil KR 100-10 C18 column (250 x 50 mm) using different proportions of acetonitrile / water as eluent carried out with 0.1% TFA.

The Reverse phase column chromatography carried out with pre-packed columns (Merck, Lobar, LiChroprep RP-18 with a peristaltic pump) using methanol / water and 0.1% acid (TFA, HCl or HBr) as Eluent.

The Flash chromatography was performed on silica gel (Merck 0-63 μm) with the carried out in the respective examples eluants.

IR spectra were taken on a Perkin Elmer 16 PC FT-IR.

example 1

4- [5-fluoro-1- (3-hydroxypropyl) indole-3-yl] -5- (5-fluoro-1-methylindol-3yl) -2,4-dihydro- [1,2,4 ] triazol-3-one

a) 5-fluoroindole-3-carboxylic acid methyl ester

To a solution of 5-fluoroindole (2.5 g, 18.5 mmol) in dioxane (75 mL) was added pyridine (14.9 mL, 185 mmol) and trichloroacetyl chloride (10.3 mL, 92.5 mmol). The resulting mixture was stirred for 2.5 hours at 80 ° C, poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water in brine, dried and evaporated. The residue was dissolved in dry methanol (100 ml) and sodium hydroxide (0.25 g) added, after which the mixture was heated to 80 ° C for 30 min. The remaining after evaporation of most of the solvent residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried and concentrated. Purification by silica gel chromatography (heptane-ethyl acetate, 3: 1/1: 1) gave 3.32 g (93%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.02 (1H, bs); 8.12 (1H, s); 7.62 (1H, dd); 7.46 (1H, dd); 7.04 (1H, dt), 3.78 (3H, s).

b) 1- (3-Benzyloxypropyl) -5-fluoroindole-3-carboxylic acid

A solution of a) (0.86 g, 4.45 mmol) and benzyl 3-bromopropyl ether (0.78 mL, 4.45 mmol) in dry DMF (20 mL) was added potassium carbonate (2.46 g, 17 , 8 mmol), after which the mixture was stirred under nitrogen overnight at room temperature. Then the mixture was partitioned between water and ethyl acetate, after which the organic phase was washed with water followed by brine and concentrated. The residue was dissolved in ethanol (15 ml) and sodium hydroxide (25%, 50 ml) was added. The reaction mixture was heated at 90 ° C for 2 hours, cooled and washed with ethyl acetate. After acidification of the aqueous phase with hydrochloric acid, the product was extracted twice with ethyl acetate. The organic layers were washed with brine, dried and concentrated to give the sub-title compound as an off-white solid (1.25 g, 86%).
¹ H-NMR (400 MHz, CDCl _3): δ 7.91 (1H, s); 7.87 (1H, dd); 7.36-7.25 (6H, m); 7.01 (1H, dt); 4.46 (2H, s), 4.30 (2H, t); 3.38 (2H); 2.15-2.11 (2H, m).

c) 1- (3-Benzyloxypropyl) -5-fluoroindole-3-carbonyl azide

A solution of b) (0.30 g, 0.92 mmol) in dichloromethane (20 ml) was treated with triethylamine (0.18 ml, 1.28 mmol) in diphenylphosphoryl azide (0.21 ml, 0.92 mmol) added.

The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by silica gel chromatography (heptane-ethyl acetate, 4: 1) to give 0.32 g (99%) of the sub-title compound as a yellow oil.
¹ H-NMR (400 MHz, CDCl _3): δ 7.90 (1H, dd); 7.81 (1H, s); 7.39-7.25 (6H, m); 7.02 (1H, dt); 4.46 (2H, s), 4.29 (2H, t); 3.38 (2H, t); 2,15-2,09 (2H, m).

d) 1- (3-Benzyloxypropyl) -5-fluoro-3-isocyanatoindole

A solution of c) (0.17g, 0.48mmol) in dry toluene (10ml) was heated at 90 ° C for 6 hours. Evaporation of the solvent gave the crude subtitle product as a yellowish oil, which was used immediately in the next step without further purification.
¹ H-NMR (400 MHz, CDCl _3): δ 7.41-7.34 (4H, m); 7.29-7.23 (3H, m); 6.99 (1H, dt); 6.90 (1H, s); 4.47 (2H, s), 4.20 (2H, t); 3.37 (2H, t); 2.09-2.04 (2H, m).

e) 4- [1- (3-Benzyloxypropyl) -5-fluoroindol-3-yl] -1- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

To a solution of d) (0.14 g, 0.44 mmol) in THF (10 mL) was added a solution of the product of Example 11e) (0.09 g, 0.44 mmol) in THF (5 mL) , The reaction mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The residue was purified by chromatography on silica (dichloromethane-methanol, 98: 2/9: 1) to give 0.18 g (75%) of the subtitled product as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.77 (1H, bs); 8.58 (1H, bs); 8.15 (1H, s); 7.91 (1H, bs); 7.82 (1H, dd), 7.55 (1H, dd); 7.50 (1H, s); 7.40 (1H, dd); 7.33-7.23 (6H, m); 7.09 (1H, dt); 6.95 (1H, dt); 4.40 (2H, s); 4:19 (2H, t); 3.86 (3H, s); 3.34 (2H, t); 1.97 (2H, m).
APCI MS m / z: 532 [MH +].

f) 4- [1- (3-Benzyloxypropyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one

A solution of e) (0.17 g, 0.33 mmol) in DMF (2 mL) was treated with triethylamine (0.21 mL, 1.48 mmol) followed by trimethylsilyl trifluoromethanesulfonate (0.24 mL, 1.32 mmol). added. The vial was sealed and heated to 130 ° C for 50 min. After cooling, the mixture was partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried and concentrated. The residue was chromatographed on silica (dichloromethane-methanol, 98: 2/95: 5) to give 0.16 g (95%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.89 (1H, bs); 7.70 (1H, dd); 7.65 (1H, s); 7.62 (1H, dd); 7.44 (1H, dd), 7.32-7.20 (5H, m); 7.09-7.03 (2H, m); 7.01 (1H, dd); 6.64 (1H, s); 4.35 (2H, s); 4.32 (2H, t); 3.50 (3H, s); 3.35 (2H, t); 2, 04 (2H, t).
APCI-MS m / z: 514 [MH +].

Compound f) (100 mg, 0.20 mmol) was dissolved in ethanol (5 ml) in acetic acid (5 ml) and then palladium (10 wt% on charcoal, 60 mg) was added. The mixture was hydrogenated overnight at normal pressure and room temperature and then filtered through Celite ^®, eluting with ethanol. The filtrate was concentrated in vacuo, after which the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and concentrated. Purification of the crude product by chromatography on silica (dichloromethane-methanol, 95: 5/9: 1) gave 51 mg (62%) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 7.75 (1H, s); 7.73 (1H, dd); 7.64 (1H, dd); 7.45 (1H, dd), 7.10-7.04 (2H, m); 6.99 (1H, dd); 6.66 (1H, s); 4.61 (1H, t); 4.31 (2H, t); 3.54 (3H, s); 3.37 (2H, dt); 1.92
(2H, m).
APCI MS m / z: 424 [MH +].

Example 2

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

a) 2- (3- {5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazole 4-yl] -indole-1-yl} -propyl) -isoindole-1,3-dione

To a solution of the product of Example 1 (80 mg, 0.189 mmol) in dry THF (10 mL) was added phthalimide (42 mg, 0.28 mmol) and triphenylphosphine (74 mg, 0.28 mmol). The mixture was cooled on an ice-bath and diethylazodicarboxylate (44 μl, 0.28 mmol) was added. Then, the reaction mixture was allowed to come to room temperature and stirred overnight. Concentration and silica gel chromatography (dichloromethane-methanol, 99: 1/98: 2/95: 5) gave 73 mg (70%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): δ 9.35 (1H, bs); 7.91 (1H, dd); 7.86-7.82 (2H, m); 7.76-7.71 (2H, m); 7.52 (1H, s), 7.31 (1H, dd); 7.15 (1H, dd); 7.05-6.97 (3H, m); 6.61 (1H, s); 4.24 (2H, t); 3.74 (2H, t); 3.53 (3H, s); 2.30 (2H, t).
APCI-MS m / z: 553 [MH +].

A mixture of a) (70 mg, 0.13 mmol) in THF (1.5 ml) and methylamine (40 wt% in water, 1.5 ml) was stirred at room temperature for 4.5 hours, concentrated in vacuo and chromatographed on silica (dichloromethane-methanol, 95: 5/9: 1 followed by dichloromethane-methanol, 9: 1 + 1% ammonium hydroxide) to give the title compound as the free amine. The amine was dissolved in as little methanol as possible and hydrochloric acid (3 M) in ethyl acetate (2 ml) was added and the resulting mixture was concentrated in vacuo and then dried under vacuum to give 30 mg (51%) of the title compound as a white Solid supplied.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 7.81 (1H, s); 7.79 (2H, bs); 7.75-7.70 (2H, m); 7.46 (1H, dd), 7.14-7.06 (2H, m); 7.03-7.0 (1H, m); 6.66 (1H, s); 4.36 (2H, t); 3.56 (3H, s); 2.76-2.64 (2H, m); 2,10-2,03 (2H, m).
APCI MS m / z: 423 [MH +]. Example 3 4- [1 - ((1S, 3S) -3-aminocyclopentyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

a) Methyl 1 (R) - [4 (S) - (tert-butyldimethylsilanyloxy) cyclopent-2-enyl] -5-fluoroindole-3-carboxylate

Sodium hydride (60% dispersion in mineral oil, 124 mg, 3.1 mmol) was weighed into a dried flask under nitrogen and mixed with dry DMF (6 ml). Then the product of Example 1a) (400 mg, 2.07 mmol) in dry DMF (4 ml) was added dropwise, after which the resulting mixture was stirred under nitrogen for 40 min at room temperature. To this was added a mixture of (1R, 4S) -4 - {[tert-butyl (dimethyl) silyl] oxy} -2-cyclopenten-1-ylacetate (530 mg, 2.07 mmol), tris (dibenzylideneacetone) dipalladium (0) (104 mg, 0.11 mmol), bis (diphenylphosphino) ethane (124 mg, 0.31 mmol), lithium chloride (catalytically effective amount) and dry DMF (10 mL). After stirring the resulting mixture under nitrogen at room temperature overnight, ethyl acetate and water were added. The organic phase was washed twice with water followed by brine, dried and concentrated. Chromatography on silica gel (heptane-ethyl acetate, 95: 5/9: 1) gave 740 mg (90%) of the sub-title compound as a yellowish oil.
¹ H-NMR (400 MHz, CDCl _3): δ 8.00 (1H, s); 7.82 (1H, dd); 7.41 (1H, dd); 6.97 (1H, dt); 6.16-6.14 (1H, m), 5.94 (1H, dd); 5.28 (1H, m); 4.88 (1H, m); 3.86 (3H, s); 2.93-2.86 (1H, m); 1.82 (1H, dt); 0.89 (9H, s); 0.11 (3H, s); 0.06 (3H, s).

b) 1 (S) - [3 (R) - (tert-Butyldimethylsilanyloxy) cyclopentyl] -5-fluoroindole-3-carboxylic acid methyl ester

To a solution of a) (740 mg, 190 mmol) in ethanol (20 mL) and ethyl acetate (20 mL) was added palladium (10 wt% on charcoal, 70 mg). The mixture was hydrogenated overnight at normal pressure and room temperature and then filtered through Celite ^®, eluting with ethyl acetate. The filtrate was concentrated in vacuo and then chromatographed on silica gel (heptane-ethyl acetate, 95: 5) to give 510 mg (69%) of the subtitled product.
¹ H-NMR (400 MHz, CDCl _3): δ 8.21 (1H, s); 7.82 (1H, dd); 7.37 (1H, dd); 6.97 (1H, dt); 4.85-4.78 (1H, m), 4.46-4.42 (1H, m); 3.86 (3H, s); 2.48-2.42 (1H, m); 2.27-2.21 (1H, m); 2.17-2.12 (1H, m); 2.01-1.97 (1H, m); 1.87-1.80 (2H, m); 0.92 (9H, s); 0.094 (3H, s); 0.092 (3H, s).

c) 1- (S) - (3 (S) -azidocyclopentyl) -5-fluoroindole-3-carboxylic acid methyl ester

A mixture of b) (270 mg, 0.69 mmol), THF (2.5 mL), water (2.5 mL) and acetic acid (6.5 mL) was heated to 70 ° C for 3.5 hours. After addition of ethyl acetate and water, the organic layer was separated and then washed with aqueous sodium bicarbonate and brine, dried and concentrated to give 190 mg of the crude alcohol. The alcohol was dissolved in dry THF (15 ml) under nitrogen. Then, diphenylphosphoryl azide (314 μl, 1.38 mmol) and triphenylphosphine (362 mg, 1.38 mmol) were added. The resulting solution was cooled on an ice bath and treated with diethyl azodicarboxylate (0.22 mL, 1.38 mmol). The reaction mixture was stirred under nitrogen for 3.5 hours at room temperature and then evaporated. Chromatography of the residue on silica (heptane-ethyl acetate, 95: 5/9: 1) yielded 167 mg (80%) of the subtitled product.
¹ H-NMR (400 MHz, CDCl _3): δ 7.87 (1H, s); 7.79 (1H, dd); 7.31 (1H, dd); 7.02 (1H, dt); 5.00-4.90 (1H, m), 4.32-4.26 (1H, m); 3.89 (3H, s); 2.50-2.05 (4H, m); 2.03-1.91 (2H, m).

d) 1- (S) - (3 (S) -azidocyclopentyl) -5-fluoroindole-3-carbonyl azide

A mixture of c) (164 mg, 0.54 mmol), ethanol (4 ml) and sodium hydroxide (25 wt%, 6 ml) was heated to 70 ° C for 1.5 hours. After cooling, the mixture was acidified with hydrogen chloride and the product extracted with ethyl acetate. The organic phase was washed twice with water, dried and concentrated. The residue was dissolved in dichloromethane and triethylamine (0.11 mL, 0.76 mmol) and diphenylphosphoryl azide (0.12 mL, 0.54 mmol) were added and the resulting mixture was stirred overnight at room temperature. Evaporation of the solvent followed by silica gel chromatography (heptane-ethyl acetate, 95: 5/9: 1) gave 144 mg (84%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): δ 7.89 (1H, dd); 7.88 (1H, s); 7.32 (1H, dd); 7.05 (1H, dt); 5.00-4.90 (1H, m), 4.33-4.27 (1H, m); 2.55-2.06 (4H, m); 2.04-1.93 (2H, m).

e) 1- (S) - (3 (S) -azidocyclopentyl) -5-fluoro-3-isocyanatoindole

The sub-title compound was prepared in analogy to Example 1d) from d) (140 mg, 0.46 mmol). The subtitle connection was used immediately in the next step.
¹ H-NMR (400 MHz, CDCl _3): δ 7.31-7.23 (3H, m); 7.04 (1H, dt); 4.96-4.92 (1H, m); 4.29-4.27 (1H, m); 2.46-2.41 (1H, m), 2.37-2.25 (2H, m); 2.15-2.06 (1H, m); 1.98-1.91 (2H, m).

f) - [1 (S) - (3 (S) -azidocyclopentyl) -5-fluoroindol-3-yl] -1- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

To a solution of e) (130 mg, 0.46 mmol) in THF (15 mL) was added portionwise the product of Example 11e) (95 mg, 0.46 mmol). After stirring at room temperature for 1 h, the solvent was evaporated and the residue chromatographed on silica (dichloromethane-methanol, 98: 2/95: 5) to give 184 mg (81%) of the subtitle product as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.76 (1H, bs); 8.57 (1H, bs); 8.15 (1H, s); 7.94 (1H, bs); 7.82 (1H, dd), 7.59 (1H, s); 7.55 (1H, dd); 7.51 (1H, dd), 7.29 (1H, dd); 7,10 (1H, dt); 6.98 (1H, dt); 5.06-5.01 (1H, m); 4.40-4.38 (1H, m); 3.87 (3H, s); 2.30-2.16 (4H, m); 1.85-1.72 (2H, m).

g) 4- [1 (S) - (3 (S) -azidocyclopentyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one

The sub-title compound was prepared in analogy to Example 1f) from f) (180 mg, 0.36 mmol) to give 85 mg (49%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.90 (1H, s); 7.93 (1H, s); 7.73-7.68 (2H, m); 7.46 (1H, dd); 7.09-6.99 (3H, m), 6.65 (1H, s); 5.19-5.14 (1H, m); 4.38-4.35 (1H, m), 3.56 (3H, s); 2,38-2,14 (4H, m); 1.88-1.70 (2H, m).
APCl-MS m / z: 447 [MH +] - N ₂ .

A mixture of g) (83 mg, 0.18 mmol), triphenylphosphine (46 mg, 0.18 mg) and pyridine (7.5 mL) was stirred at room temperature for 1.5 hours. After addition of ammonium hydroxide (25% by weight in H ₂ O, 3 ml), the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by silica gel chromatography (dichloromethane-methanol, 95: 5/9: 1/9: 1 + 1% ammonium hydroxide). The product was dissolved in as little methanol as possible and treated with hydrochloric acid (3 M) in ethyl acetate (3 ml). The resulting mixture was evaporated and then dried under vacuum overnight to give 60 mg (70%) of the title compound as an off-white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 7.96 (2H, bs); 7.93 (1H, s); 7.71-7.65 (2H, m); 7.45 (1H, dd), 7.14-7.02 (3H, m); 6.65 (1H, s); 5.27-5.23 (1H, m), 3.82-3.78 (1H, m); 3.56 (3H, s); 2.37-2.19 (4H, m); 1.96-1.91 (1H, m); 1.73-1.68 (1H, m).
APCl-MS m / z: 449 [MH +]. Example 4 4- [1 - ((1S, 3R) -3-Hydroxycyclopentyl) indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4 ] triazol-3-one

a) 1 (R) - [4 (S) - (tert-Butyldimethylsilanyloxy) cyclopent-2-enyl] -indole-3-carboxylic acid methyl ester

The sub-title compound was prepared analogously to Example 3a) starting from 1H-indole-3-carboxylic acid methyl ester (342 mg, 1.95 mmol) and acetic acid (1R, 4S) -4 - {[tert-butyl (dimethyl) silyl ] oxy} -2-cyclopenten-1-ylacetate (500 mg, 1.95 mmol), yielding 567 mg (78%).
¹ H-NMR (400 MHz, CDCl _3): δ 8.19 to 8.17 (1H, m); 7.99 (1H, s); 7.50-7.48 (1H, m); 7.26-7.24 (2H, m); 6.14 (1H, d); 5.95 (1H, d); 5.33-5.28 (1H, m); 4.89-4.88 (1H, m); 3.86 (3H, s); 2.94-2.87 (1H, m); 1.83 (1H, dt); 0.896 (9H, s); 0.112 (3H, s); 0.065 (3H, s).

b) 1 (S) - [3 (R) - (tert-Butyldimethylsilanyloxy) cyclopentyl] -1H-indole-3-carboxylic acid methyl ester

The sub-title compound was prepared in analogy to the synthetic procedure of Example 3b) starting from a) (630 mg, 169 mmol) to give 385 mg (61%).
¹ H-NMR (400 MHz, CDCl _3): δ 8.21 (1H, s); 8, 20-8, 17 (1H, m); 7.46-7.43 (1H, m); 7.27-7.22 (2H, m); 4.90-4.83 (1H, m); 4,46-4,42 (1H, m); 3.87 (3H, s); 2.50-2.43 (1H, m), 2.29-2.11 (2H, m); 2.03-1.97 (1H, m); 1.90-1.80 (2H, m); 0.93 (9H, s); 0,10 (6H, s).

c) 1 (S) - [3 (R) - (tert -butyldimethylsilanyloxy) -cyclopentyl] -indole-3-carboxylic acid

To a solution of b) (45mg, 0.12mmol) in dry toluene (3ml) was added potassium trimethylsilanolate (46mg, 0.36mmol) and the resulting mixture heated to 90 ° C under nitrogen for 2.5 hours has been. After cooling, ethyl acetate and 1 M acetic acid were added and the organic phase was washed with water and finally with brine, dried and evaporated. Silica gel chromatography (dichloromethane-methanol, 99: 1) yielded 28 mg (65%) of the subtitled product th.
¹ H-NMR (400 MHz, CDCl _3): δ 8 30 (1H, s); 8.25-8.23 (1H, m); 7.50-7.47 (1H, m); 7.30-7.24 (2H, m); 4.89-4.83 (1H, m); 4,47-4,43 (1H, m); 2.52-2.45 (1H, m); 2.30-2.18 (2H, m), 2.06-2.01 (1H, m); 1.93-1.81 (2H, m); 0.937 (9H, s); 0.088 (3H, s); 0.087 (3H, s).

d) 1 (S) - [3 (R) - (tert -butyldimethylsilanyloxy) -cyclopentyl] -indole-3-carbonylazide

The sub-title compound was prepared in analogy to Example 1c) starting from c) (28 mg, 0.08 mmol) to give 28 mg (93%).
¹ H-NMR (400 MHz, CDCl _3): δ 8.25 to 8.23 (1H, m); 8.22 (1H, s); 7.46-7.43 (1H, m); 7.28-7.20 (2H, m); 4.89-4.81 (1H, m); 4,46-4,43 (1H, m); 2.47-2.41 (1H, m); 2.30-2.22 (1H, m), 2.19-2.09 (1H, m); 2.01-1.96 (1H, m); 1.90-1.77 (2H, m); 0.920 (9H, s); 0.092 (6H, s).

e) 4- {1 (S) - [3 (R) - (tert -butyldimethylsilanyloxy) cyclopentyl] -indol-3-yl} -1- (1-methylindole-3-carbonyl) semicarbazide

A solution of d) (27 mg, 0.07 mmol) in dry toluene (3 mL) was heated to 90 ° C for 6 hours. Evaporation of the solvent gave the crude isocyanate as a yellowish oil. After addition of THF (2 ml) followed by 1-methylindole-3-carboxylic acid hydrazide, the resulting mixture was stirred for 1 hour at room temperature. Evaporation of the solvent followed by silica gel chromatography (dichloromethane-methanol, 98: 2) gave 16.5 mg (43%) of the subtitled product as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.71 (1H, bs); 8.52 (1H, bs); 8,12 (1H, d); 8.08 (1H, s); 7.90 (1H, bs); 7.56-7.47 (4H, m); 7.22 (1H, t); 7.15 (1H, t), 7.09 (1H, t); 6.98 (1H, t); 4.88-4.86 (1H, m); 4.38 (1H, m); 3.84 (3H, s); 2.07-1.67 (6H, m); 0.86 (9H, s); 0.06 (3H, s); 0.05 (3H, s).
APCI MS m / z: 546 [MH +].

A mixture of e) (13 mg, 0.023 mmol), diisopropylethylamine (20 μl, 0.12 mmol), bis (trimethylsilyl) trifluoroacetamide (30 μl, 0.12 mmol) and DMF (2 ml) was placed in a closed vial heated in a preheated oil bath at 130 ° C for 2 hours. After addition of ethyl acetate and water, the organic phase was washed with brine, dried and concentrated. The residue was chromatographed on silica gel (dichloromethane-methanol, 98: 2) to give the TBS-protected alcohol. This was dissolved in THF (200 μl), acetic acid (500 μl) and water (200 μl) and the mixture was heated at 70 ° C for 2 hours. After addition of ethyl acetate and water, the organic phase was washed with aqueous sodium bicarbonate followed by brine, dried and concentrated in vacuo. Silica gel chromatography (dichloromethane-methanol, 99: 1/98: 2/95: 5) gave 2.8 mg (29%) of the title compound as an off-white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.85 (1H, s); 8.08 (1H, d); 7.86 (1H, s); 7.69 (1H, d); 7.39 (1H, d); 7.21-7.17 (3H, m); 7.12 (1H, t); 7.01 (1H, t), 6.57 (1H, s); 5.25-5.02 (1H, m); 4.88 (1H, d); 4.27 (1H, m); 3.50 (3H, s); 2.21-1.78 (6H, m).
APCI-MS m / z: 414 [MH +].

Example 5

4,5-bis (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one

a) 5-fluoro-1-methylindole-3-carboxylic acid

The sub-title compound was prepared in analogy to Example 1b) starting from the product from Example 1a) (1.4 g, 7.25 mmol) and iodomethane (0.680 ml, 10.9 mmol), which gave 1.31 g ( 93%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.04 (1H, bs); 8.07 (1H, s); 7.63 (1H, dd); 7.53 (1H, dd); 7.08 (1H, dt); 3.83 (3H, s).

b) 5-fluoro-1-methylindole-3-carbonyl azide

The sub-title compound was prepared in analogy to Example 1c) starting from a) (400 mg, 2.07 mmol) to give 424 mg (93%).
¹ H-NMR (400 MHz, CDCl _3): δ 7.91 (1H, dd); 7.82 (1H, s); 7.29 (1H, dd); 7.08 (1H, dt); 3.86 (3H, s).

c) 5-fluoro-3-isocyanato-1-methylindole

The sub-title compound was prepared in analogy to Example 1d) starting from b) (106 mg, 0.49 mmol).
¹ H-NMR (400 MHz, CDCl _3): δ 7.24-7.19 (2H, m); 7.01 (1H, dt); 6.94 (1H, s); 3.73 (3H, s).

d) 4- (5-Fluoro-1-methylindol-3-yl) -1- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

The sub-title compound was prepared in analogy to Example 1e) starting from c) (21 mg, 0.11 mmol) and 5-fluoro-1-methylindole-3-carboxylic acid hydrazide (23 mg, 0.11 mmol) mg (50%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.75 (1H, bs); 8.56 (1H, bs); 8.14 (1H, s); 7.91 (1H, bs); 7.80 (1H, dd); 7.54 (1H, dd); 7.45 (1H, s); 7.38 (1H, dd), 7.28 (1H, dd); 7.08 (1H, dt); 6.97 (1H, dt); 3.85 (3H, s); 3.72 (3H, s).
APCI-MS m / z: 398 [MH +].

The title compound was prepared in analogy to Example 1f) starting from d) (20 mg, 0.05 mmol) to give 12.5 mg (65%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 7.76 (1H, dd); 7.74 (1H, s); 7.61 (1H, dd); 7.44 (1H, dd); 7.08 (2H, dt); 6.96 (1H, dd); 6.71 (1H, s), 3.87 (3H, s); 3.55 (3H, s).
APCI MS m / z: 380 [MH +].

Example 6

5- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -4- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

a) 1- [1- (3-Benzoyloxypropyl) -5-fluoroindol-3-yl] -4- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

The sub-title compound was prepared in analogy to Example 1e) starting from 5c) (80 mg, 0.42 mmol) and 1- (3-benzyloxypropyl) -5-fluoroindole-3-carboxylic acid hydrazide (140 mg, 0.42 mmol ), giving 185 mg (82%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.76 (1H, bs); 8.56 (1H, bs); 8.21 (1H, s); 7.91 (1H, bs); 7.81 (1H, dd); 7.56 (1H, dd); 7.45 (1H, s); 7.38 (1H, dd); 7.33-7.26 (6H, m); 7.06 (1H, t); 6.97 (1H, t); 4.44 (2H, s); 4.30 (2H, t); 3.72 (3H, s); 3.40 (2H, t); 2.06-2.03 (2H, m). APCI MS m / z: 532 [MH +].

b) 5- [1- (3-Benzyloxypropyl) -5-fluoroindol-3-yl] -4- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4] triazol-3-one

The sub-title compound was prepared in analogy to Example 1f) starting from a) (180 mg, 0.34 mmol) to give 130 mg (74%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.89 (1H, s); 7.77 (1H, dd); 7.71 (1H, s); 7.53 (1H, dd); 7.47 (1H, dd); 7.33-7.23 (3H, m); 7: 19-7, 17 (2H, m); 7.08-7.01 (2H, m); 6.91 (1H, dd); 6.68 (1H, s); 4.14 (2H, s); 4.00 (2H, t); 3.80 (3H, s); 2.99 (2H, t); 1.66-1.63 (2H, m).
APCI-MS m / z: 514 [MH +].

c) 2- (3- {5-Fluoro-3- [4- (5-fluoro-1-methylindol-3-yl) -5-oxo-4,5-dihydro- [1,2,4] triazole 3-yl] -indole-1-yl} -propyl) -isoindole-l, 3-dione

Compound b) (90 mg, 0.18 mmol) was deprotected in analogy to Example 1 to give the alcohol, which was then converted into the subtitled compound analogous to Example 2a), yielding 60 mg (32%). provided.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 7.85-7.81 (2H, m); 7.77 (1H, dd); 7.76 (1H, s); 7.62-7.49 (3H, m); 7.46 (1H, dd); 7.06 (1H, dt); 6.94 (1H, s); 6.91-6.84 (2H, m); 4.00 (2H, t); 3.85 (3H, s); 3.07 (2H, t); 1.74-1.67 (2H, m).
APCI-MS m / z: 553 [MH +].

The title compound was prepared in analogy to Example 2 starting from c) (60 mg, 0.11 mmol). The hydrochloride was obtained as an off-white solid, 31 mg (62%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.92 (1H, s); 7.74 (1H, dd); 7.72 (1H, s); 7.62-7.54 (4H, m); 7.13-7.05 (2H, m); 6.94 (1H, dd); 6.79 (1H, s); 4.05 (2H, t); 3.87 (3H, s); 2.48 (2H, t); 1.77-1.72 (2H, m).
APCI-MS m / z: 423 [MH +] (free base).

Example 7

5- (1H-indol-3-yl) -4-naphthalen-1-yl-2,4-dihydro [1,2,4] triazol-3-one

The title compound was prepared in analogy to Example 5 starting from naphthalene-1-carbonyl azide and 1H-indole-3-carboxylic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.08 (1H, s); 11.10 (1H, s); 8.21-8.16 (2H, m); 8.11 (1H, dd, J8.3 Hz); 7.68-7.74 (2H, m); 7.60 (1H, dd); 7.52-7.55 (2H, m); 7.33 (1H, d), 7,10-7,19 (2H, m); 6.13 (1H, d).
APCI-MS m / z: 328 [MH +].

Example 8

4- [1 - ((1S, 3S) -3-Aminocyclopentyl) indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

This compound was prepared in analogy to Example 3 starting from the product from Example 4 b) and 1-methylindole-3-carboxylic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 8.06 (1H, d); 7.98 (2H, bs); 7.86 (1H, s); 7.64 (1H, d); 7.40 (1H, d); 7.27-7.18 (3H, m); 7.12 (1H, dt), 7.07 (1H, dt); 6.55 (1H, s); 5.31-5.23 (1H, m); 3.94-3.70 (1H, m); 3.51 (3H, s); 2.39-2.33 (1H, m); 2.30-2.24 (3H, m); 2.01-1.93 (1H, m); 1.77-1.70 (1H, m).
APCI-MS m / z: 413 [MH +] (free base).

Example 9

4- [1 - ((1S, 3S) -3-Dimethylaminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

The product of Example 3 (0.058, 0.116 mmol) was dissolved in methanol (5 ml). To this solution was added glacial acetic acid (0.6 ml), formaldehyde (0.71 ml, 37% in water) and sodium triacetoxyborohydride (0.50 g, 2.36 mmol). Then, the flask was sealed and the mixture was stirred for 3 hours. The solvent was evaporated and the residue was purified on silica (dichloromethane-methanol, 95: 5/90: 10, followed by dichloromethane-methanol-ammonium hydroxide 75: 5: 0.5). The pure fractions were collected and evaporated. The residue was dissolved in a solution of sodium methoxide (10 ml, 0.1 M in methanol) and allowed to stand for 1 hour. After adding ammonia in water (2 ml, 25%), the solution was evaporated to dryness. The residue was purified by preparative HPLC (with trifluoroacetic acid) to give, after lyophilization, 0.045 g (66%) of the title compound.
¹ H-NMR (500 MHz, DMSO-d ₆ ): 11.94 (1H, s); 9.66 (1H, bs); 7.97 (1H, d, J 16.2 Hz); 7.76-7.68 (2H, m); 7.52-7.45 (1H, m); 7.18-7.03 (3H, m); 6.68 (1H, s); 5.16-5.10 (2H, m), 3.96-3.83 (1H, m); 3.59 (3H, s); 2.83 (6H, d, J 4.3 Hz); 2.45-2.38 (1H, m); 2.30-2.20 (2H, m); 2.03-1.93 (1H, m); 1.90-1.82 (1H, m).

Example 10

5- (indol-3-yl) -4- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one

The title compound was prepared in analogy to Example 5. 1-Methylindole-3-carbonyl azide was prepared according to Example 5b), and 1H-indole-3-carboxylic acid hydrazide was prepared according to literature procedures.
¹ H-NMR (300 MHz, DMSO-d ₆ ): 11.84 (1H, s); 11, 13 (1H, bs); 8.15 (1H, d, J 7.7 Hz); 7.70 (1H, s); 7.60 (1H, d, J 8.7 Hz); 7.36 (1H, d, J 7.8 Hz); 7.28-7.03 (5H, m); 6.57 (1H, d, J 2.9 Hz), 3.89 (3H, s). APCI MS m / z: 330.1 [MH +].

Example 11

4- [1- (3-aminopropyl) -indole-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one trifluoroacetate

a) 1- (3-bromopropyl) -indole-3-carboxylic acid methyl ester

In a flask, methyl indole-3-carboxylate (2.0 g, 11.4 mmol) and 1,3-dibromopropane (11.5 g, 57 mmol) were dissolved in 15 ml of DMF. Cesium carbonate (5.5 g, 17 mmol) was added to this solution. Then the flask was closed and the contents were stirred at 40 ° C overnight. After that, the solution became partitioned between ether and water and the ethereal phase was washed twice with water and once with brine and finally evaporated. The residue was purified on silica (heptane-ethyl acetate 4: 1) to give 2.2 g (75%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): 8.21 to 8.16 (1H, m); 7.86 (1H, s); 7.43 (1H, m); 7.32-7.28 (2H, m); 4.37 (2H, t, J 6.5 Hz); 3.91 (3H, s); 3.32 (2H, t, J 6.1 Hz); 2.39 (2H, p, J 6.2 Hz).

b) 1- (3-azidopropyl) -indole-3-carboxylic acid methyl ester

To a solution of compound a) (0.52 g, 2 mmol) in DMF (5 mL) was added sodium azide (0.14 g, 2.2 mmol). The flask was sealed and the mixture stirred overnight and then partitioned between ethyl acetate and water. The organic phase was washed twice with water and once with brine and concentrated in vacuo to give 0.48 g (93%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): 8.23 to 8.18 (1H, m); 7.83 (1H, s); 7.42-7.38 (1H, m); 7.34-7.29 (2H, m); 4.29 (2H, t, J 7.0 Hz); 3.93 (3H, s); 3.31 (2H, t, J 6.4 Hz); 2.12 (2H, p, J 6.7 Hz).

c) 1- (3-azidopropyl) -indole-3-carboxylic acid

In a flask, the compound obtained in b) (0.48 g, 1.86 mmol) was dissolved in methanol (10 ml). To this solution was added sodium hydroxide (10 ml, 1 N in water). The flask was sealed and stirred with heating to 75 ° C overnight. Then, the methanol was evaporated and the remaining aqueous solution was acidified with aqueous hydrochloric acid (2N) and extracted twice with ethyl acetate. The organic phase was washed with brine and concentrated in vacuo to give 0.36 g (80%) of the sub-title compound as a white solid.
¹ H-NMR (400 MHz, CDCl _3): 8.27 to 8.22 (1H, m); 7.92 (1H, s); 7.42-7.37 (1H, m); 7.35-7.29 (2H, m); 4.30 (2H, t, J 6.8 Hz); 3.32 (2H, t, J 6.2 Hz); 2.13 (2H, t, J 6.3 Hz).

d) 1- (3-azidopropyl) -indole-3-carbonazide

In a flask, the compound obtained in c) (0.24 g, 1.0 mmol) was dissolved in dry dichloromethane (10 ml). To this solution was added triethylamine (0.10 g, 1.0 mmol) and diphenylphosphoryl azide (0.275 g, 1.0 mmol). The flask was closed and the contents stirred overnight. The solvent was evaporated and the residue was purified on silica (heptane-ethyl acetate, 4: 1) to give 0.22 g (80%) as an oil.
¹ H-NMR (400 MHz, CDCl _3): δ 8.30 to 8.25 (1H, m); 7.84 (1H, s); 7.43-7.37 (1H, m); 7.37-7.31 (2H, m); 7.30-7.24 (1H, m); 4.28 (2H, t); 3.32 (2H, t); 2,12 (2H, p).

e) 5-Fluoro-1-methylindole-3-carboxylic acid hydrazide

In To a flask was added 5-fluoro-1H-indole (10.0 g, 74 mmol) in DMF (80 ml) dissolved. Under cooling the piston was over for a period of 10 minutes, portions of sodium hydride (60% in mineral oil, 3.6 g, 89 mmol) was added. The mixture became after complete addition stirred for another 10 minutes. Then it was over a period of 15 min. Then a period of 15 min. Iodomethane (12.6 g, 89 mmol) was added dropwise and the mixture more Stirred for 30 min. The excess sodium hydride was quenched by careful addition of water. The mixture was between ethyl acetate and water (250 + 250 ml), after which the organic phase washed twice with water and once with saline. By Stripping off the solvents 12.1 g (100%) of a solid residue was obtained.

Of the Residue (12.0 g, 74 mmol) was dissolved in 1,4-dioxane (100 ml). Then were trichloroacetyl chloride (16.5 mL, 148 mmol) and finally pyridine (14.9 mL, 185 mmol). The solution was heated to 80 ° C for 2 hours. Then the mixture was cooled, with ethyl acetate (100 ml) and with aqueous hydrochloric acid (1 N), saturated aqueous sodium bicarbonate and saline washed. The organic phase was concentrated in vacuo, which gave 31 g (100%) of a yellow solid.

The solid (74 mmol) was dissolved in 250 ml THF and treated with hydrazinium hydroxide (7.2 ml, 148 mmol). The flask was sealed and heated at 70 ° C for 2 hours to form a precipitate. The mixture was diluted with diethyl ether and the solid filtered off to give 14.0 g (91%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 9.20 (1H, bs); 7.96 (1H, s); 7.85 (1H, d); 7.60-7.48 (1H, m); 7,10 (1H, t); 4.35 (2H, bs); 3.86 (3H, s).

f) 4- [1- (3-azidopropyl) -indol-3-yl] -1- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

In a 10 ml flask, the compound obtained in d) (0.069 g, 0.26 mmol) was dissolved in 5 ml of toluene. The solution was heated to 110 ° C with stirring for 90 minutes. Then, the solution was allowed to cool and added to a suspension of the compound obtained in e) (0.050 g, 0.24 mmol) in THF (10 ml). The mixture was stirred for 1 hour and then concentrated in vacuo to give the sub-title compound as a crude product which was used without further purification.
APCI MS m / z: 449.1 [MH +].

g) 4- [1- (3-Azidopropyl) -indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one

The compound obtained in f) (0.109 g, 0.24 mmol) and DMF (5 ml) were placed in a flask. To this solution was added triethylamine (0.12 g, 1.21 mmol) and trifluoromethanesulfonic acid trimethylsilyl ester (0.27 g, 1.21 mmol). The flask was sealed and immersed in a preheated oil bath (130 ° C) and heated with stirring for 1 h. The mixture was allowed to cool and treated with ethyl acetate (15 ml) and water (15 ml). The heterogeneous mixture was stirred for 15 min. After phase separation, the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic phases were washed twice with water and once with brine and finally concentrated in vacuo. The residue was purified by silica (gradient of dichloromethane to dichloromethane-methanol, 98: 2) to give 0.088 g (85%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.89 (1H, s); 7.73-7.68 (2H, m); 7.63 (1H, d, J 8.4 Hz); 7.44 (1H, dd, J 8.8 Hz, 4.6 Hz); 7.26-7.20 (2H, m); 7.10-7.01 (2H, m); 6.70 (1H, s); 4.32 (2H, t, J 6.8 Hz); 3.53 (3H, s); 3.32 (2H, t, J 6.7 Hz); 2.05 (2H, p, J 6.6 Hz).

The compound obtained in g) (0.086 g, 0.20 mmol), triphenylphosphine (0.032 g, 0.202 mmol) and pyridine (10 mL) were placed in a flask. The flask was sealed and the contents stirred for 1 h and ammonium hydroxide (5 mL, 25% in water) added. Then the flask was closed and the mixture stirred overnight. The solution was evaporated in vacuo and the residue was purified by preparative HPLC (with trifluoroacetic acid). The pure fractions were lyophilized to give 0.050 g (49%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.89 (1H, s); 7.79-7.65 (6H, m); 7.45 (1H, dd, J 10.9 Hz, 3.8 Hz); 7.28-7.21 (2H, m); 7.11-7.02 (2H, m); 6.62 (1H, s); 4.35 (2H, t, J 6.7 Hz); 3.52 (3H, s); 2.85 (2H, m); 2.08 (2H, p, J 7.2 Hz).
APCI-MS m / z: 405.1 [MH +].

Example 12

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.90 (1H, s); 8.08 (1H, d, J 8.3 Hz); 7.81 (1H, s); 7.78-7.70 (4H, m); 7.44 (1H, d, J 8.7 Hz); 7.24 (1H, t, J 8.2 Hz); 7.18-7.10 (2H, m); 7.06-7.01 (1H, m); 6.64 (1H, s); 4.36 (2H, t, J 7.0 Hz); 3.57 (3H, s); 2.83-2.75 (2H, m); 2.08 (2H, t, J 7.2 Hz).
APCI-MS m / z: 405.1 [MH +]. Example 13 4- (8-Aminomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl) -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro [1,2,4] triazol-3-one trifluoroacetate

a) 8-Azidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole-10-carbonyl azide

In To a flask was added 8-azidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole (0.30 g, 1.32 mmol, Tetrahedron 1991, Vol. 47, No. 26, pp. 4645-4664) THF (5 ml, freshly distilled) dissolved. After addition of N, N-dimethyl-4-aminopyridine (0.001 g) became the solution chilled on an ice bath and bistrichloromethyl carbonate (0.39 g, 1.32 mmol). The batch was allowed to come to room temperature and for one hour touched. Then the mixture was concentrated in vacuo.

The residue (1.32 mmol) was dissolved in DMF (5 ml). Sodium azide (0.095 g, 1.47 mmol) was added and the mixture was stirred overnight. Then, the mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic phase was washed twice with water, once with brine, and finally evaporated, yielding an oil which was purified on silica (dichloromethane) to give 0.26 g (71%) of the sub-title compound as a white solid revealed.
¹ H-NMR (400 MHz, CDCl _3): 8.19 (1H, d, J 8.0 Hz); 7.33-7.23 (3H, m); 4.37-4.30 (1H, m); 3.97 (1H, dt, J 11.8 Hz 5.1 Hz); 3.73 (1H, dd, J 18.7 Hz 5.1 Hz); 3.57 (1H, dd, J 12.5 Hz 5.5 Hz); 3.40 (1H, dd, J 12.3 Hz 7.4 Hz); 2.91-2.81 (1H, m); 2.36-2.28 (1H, m); 2.25-2.12 (1H, m); 1.85 (1H, dq, J 12.7 Hz 6.0 Hz).

The title compound was prepared in analogy to Example 11 on the basis of the substance obtained in a) and the compound obtained from Example 11e). The title compound was obtained in the form of two diastereoisomers (rotamers) which were so stable that they could be detected by NMR at room temperature. Each rotamer is a mixture of two enantiomers. For an analogous example in which the rotamers have been isolated, see Example 69.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.92 (½H, s); 11.90 (½H, s); 7.88-7.74 (4H, m); 7.54 (1H, d, J 8.5 Hz); 7.47-7.42 (1H, m); 7.21-6.98 (4H, m); 6.66 (½H, s); 6.48 (½H, s); 4.48 (1H, t, J 14.0 Hz); 4.04 (½H, dt, J 11.8 Hz 4.8 Hz); 3.94 (½H, dt, J 11.8 Hz 4.8 Hz); 3.52 (½H, s); 3.50 (½H, s); 3.07-2.78 (3H, m); 2.38-2.10 (3H, m); 1.89-1.75 (1H, m).
APCI-MS m / z: 431.1 [MH +].

Example 14

4- (8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl) -5- (1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

The title compound was obtained in analogy to Example 13 starting from the compound obtained in Example 13a) and 1-methylindole-3-carboxylic acid hydrazide. The title compound was obtained in the form of a mixture of two diastereoisomers (rotamers) which were stable enough to be detected by NMR at room temperature (see Example 13).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.88 (½H, s); 11, 86 (½H, s); 8.17 (1H, d, J 7.8 Hz); 7.81 (3H, bs); 7.54 (1H, dd, J 8.5 Hz 2.4 Hz); 7.40 (1H, d, J 8.2 Hz); 7.25-7.00 (5H, m); 6, 62 (½H, s); 6.43 (½H, s); 4.48 (1H, t, J 14.8 Hz); 4, 04 (½H, dt, J 12.1 Hz 4.6 Hz); 3.93 (½H, dt, J 12.0 Hz 4.5 Hz); 3.51 (1½H, s); 3.49 (1½H, s); 3.07-2.80 (3H, m); 2.38-2.10 (3H, m); 1.88-1.75 (1H, m).
APCI MS m / z: 413.2 [MH +].

Example 15

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2-methyl-2,4-dihydro- [1,2 , 4] triazol-3-one hydrochloride

a) 2- (3- {5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -1-methyl-5-oxo-1,5-dihydro- [1,2, 4] triazol-4-yl] -indole-1-yl} -propyl) -isoindole-1,3-dione

In a vial, the product obtained in Example 2a) (0.030 g, 0.054 mmol) was dissolved in DMF (1.5 mL). Cesium carbonate (0.040 g, 0.12 mmol) and iodomethane (0.05 g, 0.35 mmol) were added to the solution. The vial was sealed and stirred for 2 h at room temperature. Then the mixture was partitioned between ethyl acetate and water. The organic phase was washed twice with water, once with brine and finally evaporated to give 0.035 g (100%) of the sub-title compound as a yellowish solid.
APCI-MS m / z: 567.0 [MH +].

The compound obtained in a) (0.035 g, 0.061 mmol) was dissolved in THF (8 ml) and treated with methylamine (2 ml, 40% in water). The flask was sealed and stirred for 4 h, after which it was concentrated in vacuo. The residue was purified by preparative HPLC (with hydrochloric acid) to give, after lyophilization, 0.013 g (55%) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 8.01 (3H, bs); 7.86 (1H, s); 7.82 (1H, dd, J 9.5 Hz 2.4 Hz); 7.76 (1H, dd, J 9.0 Hz 4.2 Hz); 7.51-7.46 (1H, m); 7.17-7.05 (3H, m); 6.67 (1H, s); 4.40 (2H, t, J 7.0 Hz); 3.58 (3H, s); 3.51 (3H, s); 2.84-2.74 (2H, m); 2.11 (2H, p, J 7.1 Hz).
MS-LSIMS +: m / z: 436.8 [MH +].

Example 16

4- [1- (6-aminomethyl pyridine-2-ylmethyl) -5- fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2 , 4] triazol-3-on bistrifluoroacetate

a) 1- (6-chloromethylpyridin-2-ylmethyl) -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the compound obtained in Example 1a) (0.10 g, 0.52 mmol) and 2,6-bischloromethylpyridine hydrochloride (0.41 g, 2.15 mmol) were dissolved in DMF (5 mL). After addition of potassium carbonate (0.43 g, 3.11 mmol), the flask was closed and stirred with stirring at 50 ° C for 3 h. Then the mixture was partitioned between ethyl acetate and water. The organic phase was washed twice with water and once with brine and then concentrated. The residue was purified on silica (heptane-ethyl acetate, 2: 1) to give 0.12 g (70%) of the sub-title compound as a colorless oil.
¹ H-NMR (400 MHz, CDCl _3): 7.96 (1H, s); 7.85 (1H, dd, J 9.6 Hz 2.5 Hz); 7.62 (1H, t, J 8.6 Hz); 7.40 (1H, d, J 8.2 Hz); 7.23 (1H, dd, J 9.4 Hz and 4.5 Hz); 6.98 (1H, dt, J 9.3 Hz and 2.5 Hz); 6.72 (1H, d, J 7.5 Hz); 5.45 (2H, s); 4.67 (2H, s); 3.93 (3H, s).

b) 1- (6-azidomethylpyridin-2-ylmethyl) -5-fluoroindole-3-carboxylic acid methyl ester

The product obtained in a) (0.12 g, 0.36 mmol) was dissolved in DMF (5 mL). After adding sodium azide (0.025 g, 0.38 mmol), the flask was sealed and stirred at 50 ° C for 3 hours. The mixture was partitioned between ethyl acetate and water, after which the organic phase was washed twice with water and once with brine. Evaporation gave 0.11 g (90%) of the sub-title compound as an oil.
APCI-MS m / z: 340.0 [MH +].

c) 1- (6-azidomethylpyridin-2-ylmethyl) -5-fluoroindole-3-carbonyl azide

The sub-title compound was prepared in analogy to Example 11 starting from the compound obtained in b).
FT-IR (cm ^-1 ): 2131.77; 2,100.95; 1,668.18.

The title compound was prepared in analogy to Example 11 starting from the compound obtained in c) and the compound obtained in Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.99 (1H, s); 8.21 (3H, bs); 7.99 (1H, s); 7.84 (1H, t, J 8.1 Hz); 7.72 (1H, d, J 10.8 Hz); 7.67-7.62 (1H, m); 7.48 (1H, dd, J 8.8 Hz and 4.2 Hz); 7.40 (1H, d, J 7.5 Hz); 7.14-7.03 (4H, m); 6.81 (1H, s); 5.61 (2H, s); 4:19 (2H, s); 3.57 (3H, s).
MS-LSIMS +: m / z 486.1 [MH +].

Example 17

4- [1- (3-aminomethylphenyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

a) 3- (5-Fluoroindol-1-yl) -benzamide

In a pressure-resistant container, 5-fluoroindole (1.0 g, 7.4 mmol) and 3-fluorobenzonitrile (1.1 g, 7.2 mmol) and 18-crown-6 (0.20 g) in DMSO (10 ml) dissolved. This solution was added with potassium fluoride (38% on basic alumina absorbed, 1.8 g). The container was sealed and the contents heated to 130 ° C for 1 h with stirring. Then the mixture was allowed to cool and the suspension between vinegar acid ethyl ester and water. The organic layer was washed twice with water and once with brine. The organic phase was concentrated in vacuo to a volume of approximately 15 ml. The remaining suspension was cooled on ice, after which the precipitate was filtered off and washed with ether to give 0.40 g (20%) of a white solid.
APCI MS: m / z 255.1 [MH +].

b) 3- (5-Fluoro-indol-1-yl) -benzoic acid methyl ester

The compound obtained in a) (0.40 g, 1.57 mmol) was suspended in methanol in a flask (10 ml). Dimethylformamide dimethyl acetal (4.72 mmol) was added to this suspension, after which the flask was sealed and heated to 60 ° C with stirring for 2 hours. The homogeneous solution was allowed to cool, forming a thick precipitate. The solid was filtered off to give 0.32 g (85%) of the sub-title compound as a white solid.
APCI MS: m / z 270.0 [MH +].

c) [3- (5-fluoroindol-1-yl) -phenyl] -methanol

In a flask, the compound obtained in b) (0.306 g, 1.13 mmol) was dissolved under inert atmosphere in dry THF (15 ml). After addition of lithium aluminum hydride (0.175 g, 4.6 mmol) in three portions, the mixture was stirred for 20 minutes. The mixture was refluxed for 2 hours and then allowed to cool. Thereafter, the batch was quenched by careful addition of water (166 μl), caustic soda (166 μl, 10%) and water (492 μl). The remaining solution was filtered through Celite ^® and the filtrate was concentrated in vacuo to give 0.28 g (100%) of the subtitle compound as a colorless oil.
APCI MS: m / z 242.1 [MH +].

d) 1- (3-azidomethylphenyl) -5-fluoroindole

In a flask, the compound (0.28 g, 1.16 mmol) obtained in c) was dissolved in dry dichloromethane (15 ml). Then triethylamine (0.117 g, 1.16 mmol) and methanesulfonyl chloride (0.133 g, 1.16 mmol) were added. The flask was closed and the contents stirred for 1 h. The organic solution was diluted with dichloromethane and washed with water, saturated aqueous sodium bicarbonate and brine. Evaporation of the solvent gave 0.36 g of the mesylate. The crude product was dissolved in DMF (5 ml) and sodium azide (0.08 g, 1.23 mmol) was added. The mixture was stirred for 1 h and then partitioned between ethyl acetate and water. The organic phase was washed with water, dried and evaporated to give a crude product which was purified on silica (heptane-ethyl acetate 4: 1) to give 0.29 g (94%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): 7.55 (1H, t, J 8.2 Hz); 7.50-7.44 (3H, m); 7.38 (1H, d, J 3.4 Hz); 7.35-7.29 (2H, m); 6.99 (1H, dt, J 9.2 Hz and 2.6 Hz); 6.66 (1H, d, J 3.4 Hz); 4,46 (2H, s).

e) 1- (3-azidomethylphenyl) -5-fluoroindole-3-carbonyl azide

In To a flask was obtained the compound obtained in d) (0.227 g, 0.85 mmol) in 1,4-dioxane (5 ml). These solution was treated with trichloroacetyl chloride (0.756 g, 4.16 mmol) and pyridine (0.332 g, 4.20 mmol). The flask was closed and the content for 6 hours. 70 ° C touched, after which the solution cooling down was left. Then the solution became between ethyl acetate and water and the organic phase with water, aqueous sodium bicarbonate and saline washed. By stripping off the solvent in vacuo, 0.24 g (97%) of the intermediate was obtained.

In a flask was the above intermediate (0.85 mmol) in methanol (8 ml) dissolved. This solution was added sodium hydroxide solution (10 ml, 1 N, 10 mmol). The piston was sealed and stirred 3 Hours at 70 ° C heated. Then the reaction was allowed to cool and the methanol deducted in vacuo. The resulting aqueous solution was acidified. The aqueous phase was twice with ethyl acetate extracted, after which the organic phase is dried, filtered and was evaporated, giving a brownish Solid yielded.

The solid was dissolved in dichloromethane (15 ml) and triethylamine (0.086 g, 0.85 mmol) and diphenylphosphoryl azide (0.223 g, 0.85 mmol) was added. The flask was sealed and stirred at room temperature overnight, after which the solvents were removed in vacuo. The residue was purified on silica (heptane-ethyl acetate, 5: 1), giving 0.25 g (90%) of the subtitle Compound in the form of a pale solid, which crystallized on standing.
¹ H-NMR (400 MHz, CDCl _3): 8.05 (1H, s); 7.99 (1H, dd, J 9.4 Hz and 2.6 Hz); 7.61 (1H, t, J 7.5 Hz); 7.50-7.37 (4H, m); 7.07 (1H, dt, J 9.2 Hz and 2.6 Hz); 4.50 (2H, s).

The title compound was prepared in analogy to Example 11 starting from the substance obtained in e) and the substance obtained in Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.99 (1H, s); 8.21 (3H, bs); 8.11 (1H, s); 7.79 (1H, s); 7.77-7.72 (2H, m); 7.67-7.62 (2H, m); 7.54-7.51 (1H, m); 7.49-7.44 (1H, m); 7.20-7.05 (3H, m); 6.91 (1H, s); 4.20 (2H, m); 3.60 (3H, s).

Example 18

4- [1- (3-bromopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one

The compound obtained in Example 1 (1.0 g, 2.36 mmol) was placed in acetic acid (30 ml) in a flask. Hydrobromic acid (33% in acetic acid, 8 ml) was added to this solution and the flask was sealed. Then, the flask was heated with stirring in an oil bath (80 ° C) for 12 hours. The reaction was monitored by LC-MS, confirming that the reaction was complete. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water (50 + 50 ml). The organic phase was washed twice with water and once with brine and evaporated to give 1.1 g (97%) of the title compound as a crude, which was so pure that it could be used without further purification.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.90 (1H, s); 7.76 (1H, s); 7.72-7.66 (2H, m); 7.45 (1H, dd, J 8.9 Hz and 4.4 Hz); 7.13-7.01 (3H, m); 6.74 (1H, s); 4.36 (2H, t, J 6.6 Hz); 3.57 (3H, s); 3.41 (2H, t, J 6.7 Hz); 2.32 (2H, p, J 6.7 Hz).
APCI-MS m / z: 486.1, 487.1, 488.0, 489.1 [MH +].

Example 19

4- [1- (3-bromobutyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one

The title compound was prepared analogously to Example 18 starting from 4- [5-fluoro-1- (4-hydroxybutyl) -indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro [1,2,4] triazol-3-one prepared according to the method in Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.88 (1H, s); 7.78 (1H, s); 7.73-7.67 (2H, m); 7.45 (1H, dd, J 8.7 Hz and 4.4 Hz); 7.08 (2H, tt, J 8.9 Hz and 2.7 Hz); 7.01 (1H, dd, J 9.2 Hz and 2.5 Hz); 6.65 (1H, s); 4.29 (2H, t, J 6.8 Hz); 3.58-3.52 (5H, m); 1.90 (2H, p, J 7.5 Hz); 1.74 (2H, p, J 7.2 Hz).
APCI-MS m / z: 500.0, 501.0, 502.0, 503.0 [MH +]. Example 20 2- (3- {5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazole 4-yl] -indole-1-yl} propyl) isothiourea hydrobromide

The compound obtained in Example 18 (0.064 g, 0.13 mmol), thiourea (0.030 g, 0.39 mmol) and Ethanol (99.5%, 1.5 ml) was added to a vial. The vial was sealed and heated to 75 ° C with stirring for 4 hours. The solvent was evaporated and the residue was purified on silica (dichloromethane-methanol, 95: 5 to 90:10) to give 0.061 g (82%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.96 (1H, s); 9.11 (2H, bs); 8.97 (2H, bs); 7.80 (1H, s); 7.75-7.67 (2H, m); 7.48 (1H, dd, J 9.0 Hz and 4.5 Hz); 7.16-7.02 (3H, m); 6.79 (1H, s); 4.36 (2H, t, J 7.1 Hz); 3.59 (3H, s); 3.14 (2H, t, J 7.6 Hz); 2.14 (2H, p, J 6.9 Hz).
APCI-MS: m / z 482.0, 440.0 [thiol fragment] [MH +].

Example 21

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5-benzo [b] thiophen-3-yl-2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 12.25 (1H, s); 8.38 (1H, d, J 7.9 Hz); 7.97 (1H, d, J 7.9 Hz); 7.75 (1H, s); 7.70-7.59 (4H, m); 7.48-7.37 (3H, m); 7.12-7.02 (2H, m); 4.29 (2H, t, J 6.9 Hz); 2.75-2.63 (2H, m); 2.00 (2H, p, J 7.3 Hz).
APCI MS: m / z 408.1 [MH +].

Example 22

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (indol-6-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11 starting from 1- (3-azidopropyl) -5-fluoroindole-3-carbonyl azide prepared as in Example 11d) and 1H-indole-6-carboxylic acid hydrazide (prepared by treating 1H- Indole-6-carboxylic acid methyl ester with hydrazinium hydroxide).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.98 (1H, s); 11:18 (1H, s); 7.74-7.60 (5H, m); 7.46 (1H, s); 7.41-7.35 (2H, m); 7, 06 (1H, dt, J 9.3 Hz and 2.3 Hz); 7.02-6.96 (2H, m); 6.36 (1H, s); 4.28 (2H, t, J 7.0 Hz); 2.77-2.65 (2H, m); 1.99 (2H, p, J 7.6 Hz).
APCI MS: m / z 391.1 [MH +].

Example 23

4- [1- (4-aminobutyl) indole-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.89 (1H, s); 8.10 (1H, d, J 8.4 Hz); 7.74 (1H, s); 7.70 (3H, bs); 7.66 (1H, d, J 8.5 Hz); 7.43 (1H, d, J 8.1 Hz); 7.28-7.21 (3H, m); 7.15 (1H, t, J 7.7 Hz); 7.05 (1H, t, J 7.3 Hz); 6.61 (1H, s); 4.31 (2H, t, J 7.2 Hz); 3.53 (3H, s); 2.89-2.80 (2H, m); 1.88 (2H, p, J 7.3 Hz); 1.57 (2H, p, J 7.6 Hz).
MS-LSIMS +: m / z 401.1 [MH +].

Example 24

(3- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] indol-1-yl} propylamino) methyl acetate hydrochloride

The compound obtained in Example 18 (0.050 g, 0.1 mmol), glycine methyl ester (0.08 g, 0.9 mmol) and methanol (2 mL) were placed in a vial. The vial was sealed and heated to 70 ° C overnight with stirring. The solvent was removed in vacuo and the residue was purified on silica (dichloromethane-methanol, 99: 1 to 96: 4) to give 30 mg of an oil. The oil was dissolved in methanol and treated with aqueous hydrochloric acid (1 N). The methanol was removed in vacuo and the residue was lyophilized to give the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.91 (1H, s); 9.42 (2H, bs); 7.82 (1H, s); 7.73 (2H, dt, J 9.4 Hz and 2.8 Hz); 7.46 (1H, dd, J 8.9 Hz and 4.4 Hz); 7.15-7.05 (2H, m); 7.01 (1H, dd, J 9.4 Hz and 2.4 Hz); 6.69 (1H, s); 4.38 (2H, t, J 7.2 Hz); 4.04-3.96 (2H, m); 3.72 (3H, s); 3.57 (3H, s); 3.03-2.94 (2H, m); 2.19 (2H, p, J 7.2 Hz).
APCI MS: m / z 495.2 [MH +].

Example 25

4- [1- (4-dimethylaminobutyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

In a vial The compound obtained in Example 19 (0.09 g, 0.18 mmol) in a solution of dimethylamine in ethanol (33%, 2 ml). The vial was closed and with stirring 2 Hours at 70 ° C heated. The residue remaining after evaporation of the solvent was prepared by preparative HPLC with trifluoroacetic acid cleaned.

Pure fractions were lyophilized to give 0.073 g (70%) of a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.91 (1H, s); 9,24 (1H, bs); 7.81 (1H, s); 7.75-7.68 (2H, m); 7.46 (1H, dd, J 8.9 Hz and 4.6 Hz); 7,12-7,05 (2H, m); 7.01 (1H, dd, J 9.5 Hz and 2.5 Hz); 6.69 (1H, s); 4.29 (2H, t, J 7.5 Hz); 3.55 (3H, s); 3.06-2.98 (2H, m); 2.71 (3H, s); 2.70 (3H, s); 1.80 (2H, p, J 7.4 Hz); 1.60 (2H, p, J 7.3 Hz).
APCI MS: m / z 465.2 [MH +].

Example 26

5- (5-fluoro-1-methylindol-3-yl) -4- [5-fluoro-1- (4-morpholin-4-yl-butyl) -1-indol-3-yl] -2,4- dihydro [1,2,4] triazol-3-one trifluoroacetate

The compound obtained in Example 19 (0.070 g, 0.14 mmol) and morpholine (2 ml) were placed in a vial. The vial was sealed and heated to 70 ° C with stirring for 90 min. The residue remaining in vacuo after removal of the excess morpholine was purified by preparative HPLC. The pure fractions were lyophilized to give 0.065 g (75%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.95 (1H, s); 9.59 (1H, bs); 7.84 (1H, s); 7.77-7.69 (2H, m); 7.48 (1H, dd, J 9.1 Hz and 4.5 Hz); 7.15-7.07 (2H, m); 7.04 (1H, dd, J 9.5 Hz and 2.5 Hz); 6.71 (1H, s); 4.32 (2H, t, J 6.7 Hz); 3.98-3.90 (2H, m); 3.63-3.55 (5H, m); 3.39-3.32 (2H, m); 3.14-2.96 (4H, m); 1.85 (2H, p, J 7.6 Hz); 1.69-1.60 (2H, m).
ESI + MS: m / z 507.2 [MH +].

Example 27

4- [1- (3-aminopropyl) -6-methyl-indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The compound was prepared in analogy to Example 11 starting from 6-methylindole-3-carboxylic acid methyl ester, which was prepared in analogy to Example 1a), and 1-methylindole-3-carboxylic acid hydrazide prepared according to Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.87 (1H, s); 8.10 (1H, d, J 7.8 Hz); 7.71 (3H, bs); 7.64 (1H, s); 7.48 (1H, s); 7.43 (1H, d, J 8.2 Hz); 7.23 (1H, t, J 7.5 Hz); 7.15 (1H, t, J 7.4 Hz); 7.11 (1H, d, J 8.1 Hz); 6.90 (1H, d, J 8.1 Hz); 6.59 (1H, s); 4.33 (2H, t, J 7.2 Hz); 3.54 (3H, s); 2.80 (2H, t, J 7.7 Hz); 2.44 (3H, s); 2.09 (2H, p, J 7.5 Hz).
MS-LSIMS +: m / z 401.2 [MH +].

Example 28

(3- {5-fluoro-3- [3- (5-fluoro-1-methyl-1-indol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazole 4-yl] -indole-1-yl} -propyl) trimethylammonium bromide

The compound obtained in Example 18 (0.09 g, 0.19 mmol) and trimethylamine (33% in methanol, 2 mL) were placed in a vial. The vial was sealed and heated to 85 ° C with stirring for 3 hours. The volatiles were removed in vacuo and the residue was purified by preparative HPLC to give, after lyophilization, 0.080 g (80%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.93 (1H, s); 7.85 (1H, s); 7.79-7.72 (2H, m); 7.48 (1H, dd, J 8.9 Hz and 7.5 Hz); 7.18-7.08 (2H, m); 7.05 (1H, dd, J 9.4 Hz and 2.2 Hz); 6.79 (1H, s); 4.32 (2H, t, J 7.2 Hz); 3.60 (3H, s); 3.44-3.38 (2H, m); 3.07 (9H, s); 2.35-2.24 (2H, m).
FAB MS: m / z 465.2 [MH +].

Example 29

1- (3-aminopropyl) -3- [3- (1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] -1-indole -6-carbonitrile

The title compound was prepared in analogy to Example 11 starting from 6-cyanoindole-3-carboxylic acid methyl ester prepared in analogy to Example 1a) and 1-methylindole-3-carboxylic acid hydrazide prepared in Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.97 (1H, s); 8.39 (1H, s); 8.08-8.03 (2H, m); 7.70 (3H, bs); 7.46-7.39 (3H, m); 7.23 (1H, t, J 7.7 Hz); 7.15 (1H, t, J 7.6 Hz); 6.66 (1H, s); 4.43 (2H, t, J 7.2 Hz); 3.57 (3H, s); 2.86 (2H, m); 2.09 (2H, p, J 7.5 Hz).
APCI MS: m / z 412.2 [MH +].

Example 30

4- [1- (3-aminopropyl) -5-fluoro-1-indol-3-yl] -5- (1,6-dimethylindole-3-yl) -2,4-dihydro- [1,2,4 ] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.87 (1H, s); 7.95 (1H, d, J 9.0 Hz); 7.81 (1H, s); 7.76-7.68 (4H, m); 7.23 (1H, s); 7.14 (1H, dt, J 9.1 Hz and 2.5 Hz); 7.04-6.97 (2H, m); 6.53 (1H, s); 4.36 (2H, t, J 6.5 Hz); 3.52 (3H, s); 2.82-2.74 (2H, m); 2.84 (3H, s); 2.08 (2H, p, J 7.4 Hz).
APCI MS: m / z 419.2 [MH +]. Example 31 4- [1-trans-4-aminocyclohexyl) -5-fluoro-1-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [ 1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 3 from acetic acid (1R, 4S) -4- (tert-butyldimethylsilanoxy) cyclohex-2-enyl ester prepared according to literature methods.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.92 (1H, s); 7.89 (1H, s); 7.87-7.80 (4H, m); 7.73 (1H, dd, J 10.0 Hz and 2.6 Hz); 7.47 (1H, dd, J 8.8 Hz and 4.4 Hz); 7.10 (2H, tt, J 9.1 Hz and 2.6 Hz); 7.03 (1H, dd, J 9.4 Hz and 2.5 Hz); 6.58 (1H, s); 4.52 (1H, t, J 12.1 Hz); 3.57 (3H, s); 3.18-3.07 (1H, m); 2.09 (4H, t, J 14.7 Hz); 1.90 (2H, q, J 12.1 Hz); 1.63 (2H, g, J 12.1 Hz).
APCI MS: m / z 463.2 [MH +]. Example 32 4- [1 - ((1R, 3R) -3-aminocyclopentyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 3 starting from acetic acid (1S, 4R) -4- (tert-butyldimethylsilanoxy) cyclopent-2-enyl ester.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.94 (1H, s); 7.95 (1H, s); 7.93 (3H, bs); 7.72 (1H, dd, J 10.1 Hz and 2.6 Hz); 7.67 (1H, dd, J 9.2 Hz and 4.3 Hz); 7.48 (1H, dd, J 8.9 Hz and 4.3 Hz); 7.18-7.04 (3H, m); 6.68 (1H, s); 5.23 (1H, p, J 7.2 Hz); 3.83 (1H, sec, J 6.3 Hz); 3.58 (3H, s); 2.43-2.31 (1H, m); 2.30-2.18 (3H, m); 2,02-1.90
(1H, m); 1.77-1.67 (1H, m).
MS-LSIMS +: m / z 449.2 [MH +]. Example 33 4- [1 - ((1R, 4S) -4-aminocyclopent-2-enyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro [1,2,4] triazol-3-one trifluoroacetate

a) 1 - ((4S, 1R) -4-acetoxycyclopent-2-enyl) -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the compound (6.1 g, 15.7 mmol) obtained in Example 3a) was dissolved in THF (70 ml). After adding tetrabutylammonium fluoride trihydrate (9.0 g, 28.5 mmol), the flask was sealed and stirred at room temperature for 1 hour. The solution was cooled on ice and pyridine (100 ml) in acetic anhydride (50 ml) added. After 30 minutes, the ice bath was removed and the mixture was stirred for a further 3 hours at room temperature. The volatiles were removed in vacuo and the residue was taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate (10%) and brine. The organic solution was concentrated in vacuo and the residue was purified on silica (toluene-ethyl acetate, 7: 1) to give 4.8 g (96%) of the sub-title compound as a tan solid.
¹ H-NMR (400 MHz, CDCl _3): 7.89 (1H, s); 7.81 (1H, dd), 7.38 (1H, dd); 7.07-7.00 (1H, dt); 6.32-6.28 (1H, m); 6.20-6.16 (1H, m); 5.75-5.68 (1H, m); 5.43-5.36 (1H, m); 3.89 (3H, m); 3.16-3.06 (1H, m); 1.92-1.85 (1H, m).

b) 1 - ((1R, 4S) -4-azidocyclopent-2-enyl) -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the compound obtained in a) (1.0 g, 3.15 mmol) in THF (15 ml) and water (5 ml) dissolved. After addition of sodium azide (0.4 g, 6.3 mmol), the mixture was degassed. Then, tetrakis (triphenylphosphine) palladium (0.36 g) was added and the mixture was stirred under argon for 5 hours. Thereafter, the solution was taken up with ethyl acetate and washed twice with water and once with brine. After evaporation, a yellow oil was obtained which was purified on silica (toluene-ethyl acetate, 20: 1) to give 0.83 g (87%) of the sub-title compound as a yellow oil.
¹ H-NMR (400 MHz, CDCl _3): 7.89 to 7.81 (2H, m); 7.36 (1H, dd); 7.03 (1H, dt); 6.30-6.27 (1H, m); 6.20-6.15 (1H, m); 5.46-5.39 (1H, m); 4.64-4.50 (1H, m); 3.92 (3H, s); 3.14-3.04 (1H, m); 1.96-1.88 (1H, m).

c) 1 - ((4S, 1R) -4-azidocyclopent-2-enyl) -5-fluoroindole-3-carbonyl azide

The sub-title compound was prepared in analogy to Example 11c) and 11 d) starting from the compound obtained in b).
¹ H-NMR (400 MHz, CDCl _3): 7.97 to 7.86 (2H, m); 7.36 (1H, dd); 7.07 (1H, dt); 6.36-6.29 (1H, m); 6.21-6.15 (1H, m); 5.46-5.38 (1H, m); 4.66-4.58 (1H, m); 3.15-3.04 (1H, m); 1.97-1.88 (1H, m).

d) 4- [1 - ((4S, 1R) -4-azidocyclopent-2-enyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methyl-1H-indol-3-yl ) -2,4-dihydro- [1,2,4] triazol-3-one

The sub-title compound was prepared in analogy to Example 11g) starting from the compound obtained in c) and the hydrazide described in Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.90 (1H, s); 7.75 (1H, dd, J8, Hz and 4.2 Hz); 7.69 (1H, dd, J 10.2 Hz and 2.7 Hz); 7.58 (1H, s); 7.46 (1H, dd, J 9.0 Hz and 4.5 Hz); 7.16-7.03 (3H, m); 6.70 (1H, s); 6.31-6.26 (2H, m); 5.76-5.70 (1H, m); 4.79-4.73 (1H, m); 3.59 (3H, s); 3.17-3.06 (1H, m); 1.76-1.67 (1H, m).

The title compound was prepared in analogy to Example 3 starting from the compound obtained in d).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.95 (1H, s); 8,10 (1H, bs); 7.84-7.74 (3H, m); 7.48 (1H, dd, J 8.9 Hz and 4.5 Hz); 7.17-7.04 (3H, m); 6.67 (1H, s); 6.28 (1H, d, J 5.3 Hz); 6.12 (1H, d, J 5.3 Hz); 5.84 (1H, t, J 7.5 Hz); 4.35-4.27 (1H, m); 3.53 (3H, s); 3.24-3.14 (1H, m); 1.77 (1H, p, J 6.5 Hz).
APCI MS m / z: 447.1 [MH +].

Example 34

4- [1 - ((1S, 3R) -3-aminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one trifluoroacetate

In a flask, the compound (0.02 g, 0.042 mmol) obtained in Example 33d) was dissolved in THF (4 ml) and acetic acid (1 ml). This solution was added with Pd / C (10%, 0.01 g), after which the compound was hydrogenated at normal pressure and room temperature for 3 hours. Then the solution was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC (with trifluoroacetic acid) to give, after lyophilization, 0.009 g (38%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.95 (1H, s); 7.97-7.90 (4H, m); 7.78-7.71 (2H, m); 7.48 (1H, dd, J 8.7 Hz and 4.3 Hz); 7.17-7.03 (3H, m); 6.64 (1H, s); 5.08 (1H, p, J 8.4 Hz); 3.72-3.62 (1H, m); 3.58 (3H, s); 2.76-2.65 (1H, m); 2.29-2.19 (1H, m); 2.16-2.04 (2H, m); 1.91-1.82 (2H, m).
MS-LSIMS +: m / z 449.1 [MH +].

Example 35

4- [1 - ((1R, 3S) -3-aminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 34 starting from acetic acid (1S, 4R) -4- (tert-butyldimethylsilanoxy) cyclopent-2-enyl ester.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.95 (1H, s); 7.95 (3H, bs); 7.94 (1H, s); 7.77-7.70 (2H, m); 7.48 (1H, dd, J 8.7 Hz and 4.6 Hz); 7.17-7.03 (3H, m); 6.64 (1H, s); 5.08 (1H, p, J 9.0 Hz); 3.73-3.62 (1H, m); 3.58 (3H, s); 2.77-2.67 (1H, m); 2.29-2.19 (1H, m); 2.16-2.04 (2H, m); 1.93-1.82 (2H, m).
MS-LSIMS +: m / z 449.2 [MH +].

Example 36

3- {4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5-oxo-4,5-dihydro- [1,2,4] triazol-3-yl} -1-methylindol -6-carbonitrile trifluoroacetate

The compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 12.03 (1H, s); 8.18 (1H, d, J 8.4 Hz); 8.13 (1H, s); 7.81 (1H, s); 7.77-7.67 (4H, m); 7.50 (1H, dd, J 8.4 Hz and 1.4 Hz); 7.13 (1H, dt, J 9.5 Hz and 2.4 Hz); 7.04 (1H, dd, J 9.2 Hz and 2.5 Hz); 6.95 (1H, s); 4.35 (2H, t, J 6.7 Hz); 3.66 (3H, s); 2.83-2.73 (2H, m); 2.07 (2H, p, J 7.5 Hz).
APCI MS: m / z 430.2 [MH +].

Example 37

5- (5-fluoro-1-methylindol-3-yl) -4- [5-fluoro-1- (1-methylpiperidin-4-yl) indol-3-yl] -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

a) 5-Fluoro-1- (1-methylpiperidin-4-yl) indole-3-carbonyl azide

In to a flask was 5-fluoro-1- (1-methylpiperidin-4-yl) -indole (1.0 g, 3.8 mmol, prepared according to Tetrahedron Letters 1996, p. 6045-6048) dissolved in 1,4-dioxane (25 ml). This solution was washed with pyridine (10 ml) and trichloroacetyl chloride (2.14 g, 11.4 g mmol), after which the flask was sealed. Then the Piston in an oil bath dipped and 3 hours at 80 ° C heated, after which the starting material completely reacted according to TLC was. The cooled Mixture was in ethyl acetate taken up and saturated with water aqueous sodium bicarbonate and saline which gave 1.73 g of a yellowish solid which was without further cleaning was used.

Of the Solid was dissolved in THF (50 mL) and washed with hydrazinium hydroxide (0.42 g, 8.4 mmol). The flask was sealed and left overnight stirred at room temperature. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and concentrated in vacuo, giving a brownish solid. Of the Solid was triturated with ether and pentane, yielding 0.60 g of a yellowish solid.

The solid was dissolved in acetic acid (20 ml) and water (20 ml). The solution was cooled to -10 ° C and then treated dropwise over a period of 20 minutes with a solution of sodium nitrite (0.129 g, 1.88 mmol) in water (1 ml). The resulting mixture was stirred on ice for 1 hour. Then the mixture was allowed to come to room temperature and the acetic acid was evaporated. The resulting aqueous solution was treated with sodium carbonate, after which the alkaline solution was extracted twice with acetic acid. The combined organic solutions were dried and concentrated in vacuo to give an oil which was purified on silica (dichloromethane followed by dichloromethane-methanol, 20: 1). This gave 0.35 g (28%) of the sub-title compound as a yellow solid.
¹ H-NMR (400 MHz, CDCl _3): 8.31 (1H, s); 7.77 (1H, dd); 7.72 (1H, dd); 7.15 (1H, dt); 4.47-4.32 (1H, m); 2.87 (2H, d); 2.21 (3H, s); 2.17-2.09 (2H, m); 2.07-1.80 (4H, m).

In To a flask was obtained the compound obtained in a) (0.075 g, 0.25 mmol) in toluene (5 ml). The solution was heated under nitrogen at 110 ° C for 90 minutes and then allowed to cool. The cold solution became to a suspension of the product of Example 11e) (0.051 g, 0.25 mmol) in 20 ml of THF. The mixture was stirred for 1 hour and then concentrated in vacuo.

The residue was added with xylene (8 ml), triethylamine (0.165 ml, 5 equiv.) And trifluoromethanesulfonic acid trimethylsilyl ester (0.212 ml, 5 equiv.). The flask was sealed and immersed in a preheated oil bath (130 ° C) for 1 hour. Then, the emulsion was allowed to cool and added with methanol (5 ml). The mixture was stirred for 15 minutes and then evaporated. The residue was purified on silica (dichloromethane-methanol-ammonium hydroxide, 25% in water, 90: 10: 1) to give 0.055 g of a partially purified compound. This was purified by preparative HPLC (with TFA) to give, after lyophilization, 0.045 g (31%) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.94 (1H, s); 9.56 (1H, bs); 7.90 (1H, s); 7.81-7.70 (2H, m); 7.48 (1H, dd, J 9.6 Hz and 4.4 Hz); 7.17 (1H, dt, J 9.2 Hz and 2.0 Hz); 7.11-7.05 (2H, m); 6.63 (1H, s); 4.86-4.75 (1H, m); 3.67-3.56 (2H, m); 3.59 (3H, s); 3.30-3.20 (2H, m); 2.86 (3H, s); 2.35-2.27 (2H, m); 2.21-2.07 (2H, m).
APCI MS: m / z 463.2 [MH +].

Example 38

4- [1 - ((1S, 3R) -3-Aminomethylcyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

a) 1 - ((1R, 4S) -4-ethoxycarbonyloxycyclopent-2-enyl) -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the product of Example 33a) (2.6 g, 9.25 mmol) was dissolved under nitrogen in pyridine (30 ml). The solution was cooled to 0 ° C and treated with ethyl chloroformate (1.7 g, 15.7 mmol) over a period of 10 minutes. After stirring for 1 hour at 0 ° C, the mixture was allowed to come to ambient temperature overnight. The mixture was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with saturated aqueous ammonium chloride, aqueous hydrochloric acid (1 M), saturated aqueous sodium bicarbonate and brine. The organic phase was concentrated in vacuo and the residue was purified on silica (toluene-ethyl acetate, 20: 1) to give 2.85 g (87%) of an oil which crystallized on standing.
¹ H-NMR (400 MHz, CDCl _3): 7.88 (1H, s); 7.85 (1H, dd); 7.38 (1H, dd); 7.03 (1H, dt); 6.38-6.34 (1H, m); 6.23-6.19 (1H, m); 5.70-5.65 (1H, m); 5.44-5.38 (1H, m); 4.21 (2H, q); 3.89 (3H, s); 3.23-3.13 (1H, m); 2.03-1.95 (1H, m); 1.34 (3H, t).

b) 5-Fluoro-1 - ((1R, 4R) -4-nitromethyl-cyclopent-2-enyl) -indole-3-carboxylic acid methyl ester

In a flask, the compound obtained in a) (1.25 g, 3.5 mmol) and triphenylphosphine (0.25 g, 9.6 mmol) in dichloromethane (15 mL, 3Å molecular sieve) and nitromethane (5 mL) were added. solved. The solution was degassed and kept under argon and treated with Pd ₂ (dba) ₃ (0.18 g, 1.96 mmol). After stirring under argon overnight, the mixture was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed twice with water and once with brine. Evaporation of the organic phase gave a crude product which was purified on silica (toluene-ethyl acetate, 4: 1) to give 0.70 g (64%) of the sub-title compound as a colorless oil.
¹ H-NMR (400 MHz, CDCl _3): 7.86 to 7.82 (2H, m); 7.33 (1H, dd); 7.04 (1H, dt); 6.23-6.18 (1H, m); 6.14-6.11 (1H, m); 5.59-5.52 (1H, m); 4.57-4.48 (1H, m); 4.42-4.33 (1H, m); 3.94 (3H, s); 3.68-3.57 (1H, m); 3.05-2.94 (1H, m); 1.75-1.64 (1H, m).

c) 1 - ((1S, 3R) -3-aminomethylcyclopentyl) -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the compound obtained in b) (0.70 g, 2.16 mmol) was dissolved in ethanol (25 ml, 95%), ethyl acetate (25 ml) and acetic acid (3 ml). Palladium (5% on charcoal, 0.33 g) was added and the mixture was hydrogenated at atmospheric pressure and room temperature for 48 hours. The mixture was filtered and the filtrate concentrated in vacuo. The residue was taken up in ethyl acetate and washed with sodium hydroxide (1 M, aq.), Water and brine. The solution was concentrated in vacuo and the residue was purified on silica (dichloromethane-methanol-ammonium hydroxide, 25% in water, 90: 10: 1) to give 0.60 g (96%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): 8.02 (1H, s); 7.81 (1H, dd); 7.32 (1H, dd); 7.02 (1H, dt); 4.80-4.70 (1H, m); 3.93 (3H, s); 3.51 (2H, s); 2.93-2.85 (2H, m); 2.58-2.48 (1H, m); 2.38-2.25 (2H, m); 2.09-1.93 (2H, m); 1.75-1.62 (2H, m).

d) 1 - [(1S, 3R) -3- (tert-Butyloxycarbonylaminomethyl) cyclopentyl] -5-fluoroindole-3-carboxylic acid methyl ester

In a flask, the compound obtained in c) (0.70 g, 2.4 mmol) was dissolved in THF (50 ml) and the solution was cooled on an ice bath. Di-tert-butyl dicarbonate (0.80 g, 3.67 mmol) was added and the flask was closed and stirred for 3 hours. The solvent was removed in vacuo and the residue was purified on silica (toluene-ethyl acetate, 10: 1) to give 0.9 g (100%) of the subtitle compound as a colorless oil.
¹ H-NMR (400 MHz, CDCl _3): 7.97 (1H, s); 7.83 (1H, dd); 7.32 (1H, dd); 7.03 (1H, dt); 4.74 (1H, p); 3.92 (3H, s); 3.26-3.16 (2H, m); 2.53-2.44 (1H, m); 2.38-2.26 (2H, m); 2.07-1.96 (2H, m); 1.69-1.58 (2H, m); 1.46 (9H, s).

e) 1 - [(1S, 3R) -3- (tert-butyloxycarbonylaminomethyl) cyclopentyl] -5-fluoroindole-3-carbonyl azide

The compound was prepared in analogy to Example 11c) and Example 11d) starting from the compound obtained in d).
¹ H-NMR (400 MHz, CDCl _3): 7.98 (1H, s); 7.91 (1H, dd); 7.34 (1H, dd); 7.05 (1H, dt); 4.75 (1H, p); 3.24 (2H, d); 2.54-2.46 (1H, m); 2.41-2.27 (2H, m); 2.06-1.95 (2H, m); 1.72-1.60 (2H, m).

In In a flask, the compound obtained in e) (0.081 g, 0.20 mmol) in toluene (5 ml). The solution was heated under nitrogen at 110 ° C for 90 minutes and then allowed to cool. This cold solution became to a suspension of the product of Example 11e) (0.047 g, 0.23 mmol) in THF (20 ml). The mixture was stirred for 1 hour and concentrated in vacuo.

The residue was added with xylene (8 ml), triethylamine (0.140 ml, 5 equiv.) And trifluoromethanesulfonic acid trimethylsilyl ester (0.180 ml, 5 equiv.). The flask was sealed and immersed in a preheated oil bath (130 ° C) for 1 hour. Then, the emulsion was allowed to cool and added with methanol (5 ml). The mixture was stirred for 15 minutes and evaporated. The residue was purified on silica (dichloromethane-methanol-ammonium hydroxide, 25% in water, 90: 10: 1) to give 0.090 g of a partially pure compound. This was further purified by preparative HPLC (with trifluoroacetic acid) to give, after lyophilization, 0.055 g (48%) of the title compound as a pale solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.93 (1H, s); 7.96 (1H, s); 7.79-7.70 (5H, m); 7.48 (1H, dd, J 9.3 Hz and 4.6 Hz); 7.10 (2H, tt, J 8.9 Hz and 2.2 Hz); 7.03 (1H, dd, J 9.3 Hz and 2.2 Hz); 6.63 (1H, s); 5.08 (1H, p, J 8.8 Hz); 3.57 (3H, s); 2.91 (2H, p, J 2.9 Hz); 2.48-2.40 (1H, m); 2.35-2.20 (2H, m); 1.97-1.86 (2H, m); 1.70-1.55 (2H, m).
APCI MS: m / z 463.2 [MH +].

Example 39

4- [1 - ((1S, 3R) -3-Dimethylaminomethylcyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

The compound obtained in Example 38 (0.08 g, 0.12 mmol) and sodium triacetoxyborohydride (0.94 g, 4.4 mmol) were placed in a flask. After adding a mixture of methanol (9 ml), acetic acid (1 ml) and formaldehyde (1.2 ml, 37% in water), the flask was closed and the contents were stirred for 3 hours. The volatiles were removed in vacuo and the residue was purified on silica (dichloromethane-methanol-ammonium hydroxide, 25% in water, 90: 10: 1). The pure fractions were collected and evaporated. The residue was dissolved in a solution of sodium methoxide (10 ml, 0.1 M in methanol) and allowed to stand for 1 hour. Then ammonia (2 mL, 25% in water) was added and the solution was evaporated to dryness. The residue was purified by preparative HPLC (with trifluoroacetic acid) to give, after lyophilization, 0.055 g (76%) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.93 (1H, s); 9,22 (1H, bs); 7.95 (1H, s); 7.77-7.71 (2H, m); 7.48 (1H, dd, J 8.6 Hz and 4.5 Hz); 7.11 (2H, qt, J 9.2 Hz and 2.6 Hz); 7.04 (1H, dd, J 9.2 Hz and 2.6 Hz); 6.64 (1H, s); 5.07 (1H, p, J 7.8 Hz); 3.57 (3H, s); 3.18 (2H, t, J 6.2 Hz); 2.84-2.78 (6H, m); 2.55-2.41 (2H, m); 2.30-2.18 (1H, m); 2.03-1.87 (2H, m); 1.72-1.54 (2H, m). APCI MS: m / z 491.2 [MH +].

Example 40

4- [1 - ((1S, 3R) -3-Dimethylaminomethylcyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2-hydroxymethyl-2,4- dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared according to Example 39 without treatment with sodium methoxide in methanol.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 9, 14 (1H, bs); 7.99 (1H, s); 7.87 (1H, dd, J 10.1 Hz and 2.5 Hz); 7.78-7.71 (2H, m); 7.48 (1H, dd, J 9.0 Hz and 4.5 Hz); 7.13 (2H, m); 7.04 (1H, dd, J 9.3 Hz and 2.3 Hz); 6.64 (1H, s); 5.20 (2H, s); 5.08 (1H, p, J 8.1 Hz); 3.58 (3H, s); 3.18 (2H, t, J 6.0 Hz); 2.80 (6H, m); 2.54-2.40 (2H, m); 2.34-2.20 (1H, m); 2.02-1.88 (2H, m); 1.72-1.52 (2H, m).
APCI MS: m / z 521.2 and 491.2 [MH +].

Example 41

5- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] - indol-1-yl} -pentanamidintrifluoracetat

In a vial, the compound obtained in Example 19 (0.080 g, 0.16 mmol) was dissolved in DMF (2 mL) and sodium cyanide (0.050 g, 1.02 mmol) was added. The vial was sealed and placed under Stirring 2 hours (50 ° C). The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine and evaporated to give the crude nitrile.

The Nitrile was in a freshly prepared solution of hydrochloric acid in ethanol (saturated) dissolved in a flask. The flask was sealed and stirred overnight. By Subtracting the volatile Components in vacuo became a partially crystalline crude iminoester receive.

The crude iminoester was dissolved in a solution of ammonia in methanol. The solution was stirred for 3 hours and the reaction was monitored by HPLC. The mixture was then evaporated and the residue purified by preparative HPLC (with trifluoroacetic acid) to give 0.050 g (54%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.94 (1H, s); 8.86 (2H, bs); 8.49 (2H, bs); 7.82 (1H, s); 7.73 (1H, dd, J 10.2 Hz and 2.6 Hz); 7.68 (1H, dd, J 9.0 Hz and 4.3 Hz); 7.47 (1H, dd, J 8.8 Hz and 4.6 Hz); 7.11 (2H, tt, J 9.2 Hz and 2.6 Hz); 7.03 (1H, dd, J 9.4 Hz and 2.4 Hz); 6.71 (1H, s); 4.30 (2H, t, J 7.2 Hz); 3.57 (3H, s); 2.38 (2H, t, J 7.6 Hz); 1.82 (2H, p, J 7.5 Hz); 1.61 (2H, p, J 7.5 Hz).
APCI MS: m / z 464.2 [MH +].

Example 42

5- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] - indol-1-yl} -butanamidin trifluoroacetate

The title compound was prepared in analogy to Example 41 starting from the compound obtained in Example 18.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.94 (1H, s); 8.93 (2H, bs); 8.61 (2H, bs); 7.81 (1H, s); 7.76 (1H, dd, J 10.1 Hz and 2.6 Hz); 7.68 (1H, dd, J 9.0 Hz and 4.3 Hz); 7.48 (1H, dd, J 8.9 Hz and 4.6 Hz); 7.16-7.02 (3H, m); 6.75 (1H, s); 4.31 (2H, t, J 7.0 Hz); 3.57 (3H, s); 2.46-2.40 (2H, m); 2.16 (2H, p, J 7.7 Hz).
APCI MS m / z: 450.2 [MH +].

Example 43

5- [1- (3-aminopropyl) indol-3-yl] -4- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate a) 1- (3-azidopropyl) indole-3-carboxylic acid hydrazide

In a flask, the compound obtained in Example 11c) (0.354 g, 1.45 mmol) and N-hydroxysuccinimide (0.20 g, 1.74 mmol) and dimethylaminopyridine (0.02 g, 0.16 mmol) in dry Dichloromethane (10 ml). To the stirred solution was added dicyclohexylcarbodiimide (0.355 g, 1.70 mmol). After 1 min, a precipitate was obtained but the reaction was allowed to continue overnight. After addition of hydrazinium hydroxide (0.30 g, 6.0 mmol), the mixture was stirred for a further 30 min. The solvent was removed in vacuo and the residue was purified on silica (dichloromethane-methanol, gradient from 99: 1 to 96: 4) to give 0.34 g (91%) of the sub-title compound.
APCI MS m / z: 259.0 [MH +].

b) 1- [1- (3-azidopropyl) indole-3-carbonyl] -4- (1-methylindol-3-yl) semicarbazide

1-Methylindole-3-carbonyl azide (0.038 g, 0.19 mmol, prepared according to Example 5b) was added to a flask in toluene (5 mL). The solution was heated to 110 ° C for 1 h and then allowed to cool. The cold solution was added to a solution of the compound obtained in a) (0.05 g, 0.19 mmol) in 10 ml of THF. After a few minutes, a precipitate had formed. The mixture was stirred for a further 30 min, after which the precipitate was centrifuged off. The supernatant was discarded and the solid dried in vacuo to give 0.064 g (75%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 9.74 (1H, bs); 8.57 (1H, bs); 8, 16-8, 11 (2H, m); 7.91 (1H, bs); 7.55 (2H, t, J 7.8 Hz); 7.40 (1H, s); 7.36 (1H, d, J 8.9 Hz); 7.22 (1H, t, J 7.7 Hz); 7.18-7.10 (2H, m); 7.00 (1H, t, J 7.5 Hz); 4.29 (2H, t, J 6.8 Hz); 3.71 (3H, s); 3.37 (2H, t, J 6.7 Hz); 2.03 (2H, p, J 6.8 Hz).
APCI-MS m / z: 431.0 [MH +].

c) 5- [1- (3-azidopropyl) indol-3-yl] -4- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one

The compound obtained in b) (0.062 g, 0.14 mmol) and 3 ml of DMF were placed in a flask. This solution was then added with triethylamine (0.073 g, 0.72 mmol) and trifluoromethanesulfonic acid trimethylsilyl ester (0.16 g, 0.72 mmol). The flask was sealed and stirred in a preheated oil bath (130 ° C) for 1 h. The mixture was allowed to cool and treated with ethyl acetate (15 ml) and water (15 ml). The heterogeneous mixture was stirred for 15 min. After phase separation, the aqueous phase was extracted with ethyl acetate (15 ml). The combined organic phases were washed twice with water and once with brine and finally evaporated. The residue was purified on silica (gradient of dichloromethane to dichloromethane-methanol, 98: 2) to give 0.043 g (72%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.89 (1H, s); 8.13 (1H, d, J 7.8 Hz); 7.70 (1H, s); 7.59 (1H, d, J 8.4 Hz); 7.47 (1H, d, J 8.1 Hz); 7.23 (2H, t, J 9.2 Hz); 7.16 (1H, t, J 7.5 Hz); 7.11 (1H, d, J 7.5 Hz); 7.00 (1H, t, J 7.5 Hz); 6, 59 (1H, s); 3.96 (2H, t, J 6.5 Hz); 3.90 (3H, s); 2.78 (2H, t, J 6.8 Hz); 1.61 (2H, p, J 6.7 Hz).
APCI MS m / z: 413.0 [MH +].

Compound c) (0.042 g, 0.10 mmol) was dissolved in ethanol (5 mL, 99.5%) and acetic acid (5 mL). Palladium on carbon (0.010 g, 10% Pd on C) was added and the compound was hydrogenated at room temperature under normal pressure for 3 hours. After filtering off the catalyst through Celite ^®, the filtrate was concentrated in vacuo. The residue was purified on silica (dichloromethane-methanol-ammonium hydroxide, 25% in water, 90: 10: 2). The purified product was then dissolved in methanol and water. After addition of trifluoroacetic acid, the methanol was evaporated and the remaining aqueous solution was lyophilized to give 0.025 g (50%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.90 (1H, s); 8.09 (1H, d, J 8.4 Hz); 7.66 (1H, s); 7.57 (1H, d, J 9.5 Hz); 7.60-7.52 (3H, bs); 7.49 (1H, d, J 8.3 Hz); 7.22 (1H, t, J 9.5 Hz); 7.14 (1H, t, J 7.9 Hz); 7.00 (1H, t, J 7.9 Hz); 6.68 (1H, s); 3.99 (2H, t, J 7.0 Hz); 3.87 (3H, s); 2.43 (2H, m); 1.71 (2H, p, J 7.0 Hz). APCI MS m / z: 387.2 [MH +].

Example 44

4- [1- (3-aminopropyl) -5-methylindole-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

a) 5-methylindole-3-carboxylic acid methyl ester

The sub-title compound was prepared in analogy to Example 1a) from 5-methyl-1H-indole.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.80 (1H, bs); 8.00 (1H, s); 7.79 (1H, t, J 0.8 Hz); 7.35 (1H, d, J 8.4 Hz); 7.02 (1H, dd, J 8.4 Hz and 1.5 Hz); 3.79 (3H, s); 2.40 (3H, s).

b) 1- (3-tert-Butoxycarbonylaminopropyl) -5-methyl-1H-indole-3-carboxylic acid methyl ester

A mixture of the subtitle compound a) (217 mg, 1.2 mmol), 3-t-butoxycarbonylaminopropylbromide (656 mg, 2.8 mmol) and potassium carbonate (380 mg, 2.8 mmol) in dry DMF (7 mL) Stirred for 16 h at room temperature and then partitioned between ethyl acetate and water. The organic phase was washed with water, saturated aqueous sodium chloride and water, dried and concentrated. The residue was subjected to silica gel flash chromatography (heptane-ethyl acetate, 5: 2) to give the sub-title compound (280mg, 70%).
¹ H-NMR (400 MHz, CDCl _3): δ 7.98 (1H, s); 7.79 (1H, s); 7.24 (1H, d, J 8.4 Hz); 7.12 (1H, dd, J 8.4 Hz and 1.3 Hz); 4.54 (1H, bs); 4.18 (2H, t, J 7.0 Hz); 3.91 (3H, s); 3.13 (2H, m); 2.50 (3H, s); 2.06 (2H, p, J 6.8 Hz); 1.45 (9H, s).

c) [3- (3-Azidocarbonyl-5-methylindol-1-yl) -propyl] -carbamic acid tert-butyl ester

The sub-title compound was prepared in analogy to Example 1c) starting from b).
¹ H-NMR (400 MHz, CDCl _3): δ 8.05 (1H, s); 7.82 (1H, s); 7.25 (1H, d, J 8.4 Hz); 7.14 (1H, dd, J 8.4 Hz and 1.4 Hz); 4.62 (1H, bs); 4.18 (2H, t, J 7.0 Hz); 3.15 (2H, m); 2.50 (3H, s); 2.26 (2H, p, J 6.8 Hz); 1.46 (9H, s).

d) [3- (3-Isocyanato-5-methylindol-1-yl) -propyl] -carbamic acid tert-butyl ester

A solution of c) (138 mg, 0.4 mmol) in toluene (8 mL) was heated at reflux for 3 h and then concentrated to give the sub-title compound (120 mg, 78%).
¹ H-NMR (400 MHz, CDCl _3): δ 7.36 (1H, s); 7.19 (1H, d, J 8.2 Hz); 7.08 (1H, dd, J 8.6 Hz and 1.0 Hz); 6.92 (1H, s); 4.53 (1H, m); 4, 07 (2H, t, J 6.9 Hz); 3.09 (2H, m); 2.47 (3H, s); 1.97 (2H, p, J 6.8 Hz); 1.44 (9H, s).

e) 4- [1- (3-tert-Butoxycarbonylaminopropyl) -5-methylindol-3-yl] 1-1 (1-methylindole-3-carbonyl) semicarbazide

A solution of 1-methyl-1H-indole-3-carboxylic acid hydrazide (105 mg, 0.6 mmol) in dry DMF (1.5 mL) was added to a solution of compound d) (120 mg, 0.4 mmol) in dry dioxane (8 ml). The mixture was stirred at room temperature for 16 h and then partitioned between ethyl acetate and water. The organic phase was washed three times, dried and concentrated. The residue was subjected to silica gel flash chromatography (dichloromethane-methanol, 25: 1). The fractions containing the subtitled compound were combined, concentrated, dissolved in chloroform and methanol, and diethyl ether was added to precipitate the sub-title compound (140 mg, 75%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.73 (1H, bs); 8.52 (1H, bs); 8.14 (1H, d, J 7.8 Hz); 8,10 (1H, s); 7.88 (1H, bs); 7.52 (1H, d, J 8.2 Hz); 7.42 (1H, s); 7.33 (1H, s); 7.29 (1H, d, J 8.2 Hz); 7.24 (1H, t, J 6.8 Hz); 7.17 (1H, t, J 7.2 Hz); 6.95 (1H, d, J 8.8 Hz); 6.93 (1H, m); 4.08 (2H, t, J 6.8 Hz); 3.86 (3H, s); 2.89 (2H, m); 2.38 (3H, s); 1.80 (2H, p); 1.36 (9H, s).
APCI-MS m / z: 419 [MH +] -t-Boc.

A mixture of compound e) (98 mg, 0.19 mmol), triethylamine (91 mg, 0.9 mmol) and trimethylsilyl trifluoromethanesulfonate (200 mg, 0.9 mmol) and DMF (3 mL) were placed in a sealed tube for 3 h heated to 130 ° C. The oily residue remaining after concentration of the mixtures was treated with 2N sodium hydroxide (2 ml) and stirred at 80-100 ° C. for 1 h. The crude product was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt (70 mg, 72%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 8.12 (1H, d, J 7.8 Hz); 7.79 (3H, bs); 7.68 (1H, s); 7.58 (1H, d, J 8.4 Hz); 7.44 (1H, d, J 8.2 Hz); 7.24 (1H, m); 7.16 (1H, m); 7.09 (1H, d, J 8.4 Hz); 7.03 (1H, s); 6.58 (1H, s); 4.34 (2H, t, J 6.8 Hz); 3.54 (3H, s); 2.80 (2H, m); 2.31 (3H, s); 2.08 (2H, p, J 6.8 Hz).
APCI MS m / z: 401 [MH +].

Example 45 4- [1- (3-Aminopropyl) -5-fluoroindol-3-yl] -5- (1H-pyrrolo [2,3-b] pyridin-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one hydrochloride.

a) 2,2,2-Trichloro-1- (1H-pyrrolo [2,3-b] pyridin-3-yl) ethanone

A mixture of 7-azaindole (2.03 g, 17.2 mmol) and trichloroacetyl chloride (4.06 g, 20.6 mmol) was heated to 110 ° C in a sealed tube for 30 min and then cooled to rt. The crude product was dissolved in as little ethanol as possible and mixed with chloroform to induce crystallization. The crystalline substance was filtered (2.21 g) and recrystallised from ethanol to give the pure sub-title compound (1.15 g, 25%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 13.16 (1H, bs); 8.68 (1H, s); 8.51 (1H, dd, J 7.8 Hz and 1.5 Hz); 8.42 (1H, dd, J 4.6 Hz and 1.5 Hz); 7.38 (1H, dd, J 7.8 Hz and 4.6 Hz). APCI-MS m / z: 263 [MH +]; and 265 [MH2 +].

b) 1H-Pyrrolo [2,3-b] pyridine-3-carboxylic acid hydrazide

A mixture of compound a) (1.04 g, 3.9 mmol) and hydrazine hydrate (0.30 g, 5.9 mmol) in dry THF (30 mL) was heated at reflux for 1.5 h. The solid product was filtered off and washed several times with THF and then with diethyl ether to give the sub-title compound (0.56 g, 81%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.05 (1H, bs); 9,26 (1H, s); 8.42 (1H, bd, J 7.8 Hz); 8.26 (1H, bd, J 4.6 Hz); 8.08 (1H, s); 7.16 (1H, ddd, J 7.8 Hz and 4.7 Hz); 4.33 (2H, s).
APCI MS m / z: 177 [MH +].

c) 3- (3-Azidocarbonyl-5-fluoroindol-1-yl) propyl] -carbamic acid tert-butyl ester

The sub-title compound was prepared in analogy to Example 44c) starting from 5-fluoroindole.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (1H, s); 7.73 (1H, dd, J 9.7 Hz and 2.5 Hz); 7.69 (1H, dd, J 9.1 Hz and 4.5 Hz); 7.18 (1H, m); 6.97 (1H, m); 4.29 (2H, m); 2.90 (2H, m); 1.88 (2H, m); 1.37 (9H, s).

d) [3- (5-Fluoro-3-isocyanatoindol-1-yl) propyl] -carbamic acid tert-butyl ester

The sub-title compound was prepared as in the synthesis of compound 44d) from c).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.58 (1H, s); 7.53 (1H, dd, J 9.1 Hz and 4.3 Hz); 7.25 (1H, bd); 7.06 (1H, m); 6.91 (1H, m); 4,12 (2H, m); 2.86 (2H, m); 1.80 (2H, m); 1.35 (9H, s).

e) 4- [1- (3-tert-Butoxycarbonylaminopropyl) -5-fluoroindol-3-yl] -1- (7-azaindole-3-carbonyl) semicarbazide

A suspension of subtitled compound b) (98mg, 0.56mmol) in dry DMF (5mL) was added to a solution of compound d) (233mg, 0.56mmol) in dry dioxane (5mL) followed by stirring Mixture was stirred for 1.5 h at rt and then partitioned between ethyl acetate and water. The organic layer was washed twice with water and then concentrated. The solid residue was triturated with toluene and filtered to give the sub-title compound (200 mg, 70%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.19 (1H, bs); 9.86 (1H, bs); 8.60 (1H, bs); 8.44 (1H, d, J 7.8 Hz); 8.30 (1H, d, J 4.4 Hz); 8.26 (1H, s); 7.94 (1H, bs); 7.54 (1H, s); 7.44 (1H, dd, J 7.8 Hz and 4.4 Hz); 7.30 (1H, m); 7.20 (1H, m); 6.92-7.00 (2H, m); 4.12 (2H, t, J 6.4 Hz); 1.82 (2H, m); 1.37 (s, 9H).

A mixture of subtitle compound e) (99 mg, 0.19 mmol), trifluoromethanesulfonic acid trimethylsilyl ester (345 mg, 1.55 mmol) and triethylamine (157 mg, 1.55 mmol) in dry DMF (5 mL) were placed in a sealed tube 15 Heated to 130 ° C, cooled to rt. And partitioned between ethyl acetate and water. The aqueous phase was basified (pH 10) and extracted with ethyl acetate and then with a mixture of dichloromethane and methanol (3: 1 by volume). The organic extracts were combined and concentrated. The residue was triturated with ethyl ether, after which the solid was filtered off and subjected to silica gel flash chromatography (dichloromethane-methanol-ammonium hydroxide, 150: 15: 2 and then 150: 20: 2). The free amine-containing fractions were combined and concentrated. The residue was dissolved in 0.2 N hydrochloric acid (20 ml) and lyophilized to give the title compound (28 mg, 34.6%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (1H, s); 11.82 (1H, bs); 8.40 (1H, dd, J 8, 0 Hz and 1.6 Hz); 8.30 (1H, dd, J 4.8 Hz and 1.5 Hz); 7.87 (4H, m); 7.74 (1H, dd, J 9.0 Hz and 4.3 Hz); 7.2 (1H, dd, J 8.0 Hz and 4.8 Hz); 7.14 (1H, dt, J 9.2 Hz and 1.5 Hz); 7.07 (1H, dd, J 9.4 Hz and 2.4 Hz); 6.66 (1H, d, J 2.8 Hz); 4.39 (2H, t, J 6.8 Hz); 2.80 (2H, m); 2.08 (2H, m).
APCI-MS m / z: 392 [MH +].

Example 46

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (4-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 45 from 4-fluoro-1-methyl-1H-indole-3-carboxylic acid hydrazide and 45 d).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.97 (1H, s); 7.65 (2H, bs); 7.58 (1H, s); 7.52 (1H, s); 7.52 (1H, m); 7.25 (1H, d, J 8.2 Hz); 7,10 (1H, m); 7.02 (1H, dd, J 9.2 Hz and 2.4 Hz); 6.98 (1H, dd, J 5.7 Hz and 2.4 Hz); 6.96 (1H, dd, J 9.4 and 2.4 Hz); 6.78 (1H, dd, J 11.2 and 7.8 Hz); 4.20 (2H, t, J 6.6 Hz); 3.72 (3H, s); 2.64 (2H, m); 1.91 (2H, m).
APCI MS m / z: 423 [MH +].

Example 47

4- [1- (3-aminopropyl) indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11 from 1-methyl-1H-indole-3-carboxylic acid hydrazide and 11d).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.92 (1H, s); 8,12 (1H, d); 7.79 (3H, bs); 7.77 (1H, s); 7.71 (1H, d); 7.45 (1H, d); 7.29 (1H, dd); 7.25 (1H, d); 7.25 (1H, dd); 7.18 (1H, dd); 7.09 (1H, dd); 6.62 (1H, s); 4.40 (2H, t); 3.56 (3H, s); 2.88-2.78 (2H, m); 2,12 (2H, p).
APCI-MS m / z: 387 [MH +].

Example 48

4- [1- (2-aminoethyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.96 (1H, s); 8.03 (3H, bs); 7.72 (1H, s); 7.81 (1H, dd); 7.73 (1H, dd); 7.50 (1H, dd); 7.19 (1H, dt); 7.13 (1H, dt); 7.09 (1H, dd); 6.91 (1H, s); 4.50 (2H, t); 3.63 (3H, s); 3.40-3.30 (2H, m).
APCI-MS m / z: 409 [MH +].

Example 49

4- [1- (4-aminobutyl) -5-fluoroindole-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.96 (1H, s); 7.84 (1H, s); 7.78 (1H, dd); 7.75 (3H, bs); 7.72 (1H, dd); 7.50 (1H, dd); 7.13 (2H, dt); 7.05 (1H, dd); 6.71 (1H, s); 4.32 (2H, t); 3.59 (3H, s); 2.88-2.83 (2H, m); 1.85-1.93 (2H, m); 1.61-1.54 (2H, m).
APCI-MS m / z: 437 [MH +].

Example 50

4- [1- (5-aminopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.96 (1H, s); 7.82 (1H, s); 7.74 (1H, dd); 7.70 (3H, bs); 7.70 (1H, dd); 7.49 (1H, dd); 7,12 (2H, dt); 7.05 (1H, dd); 6.74 (1H, s); 4.28 (2H, t); 3.59 (3H, s); 2.79-2.74 (2H, m); 1.87-1.79 (2H, m); 1.60-1.53 (2H, m); 1.35-1.28 (2H, m). APCI MS m / z: 451 [MH +].

Example 51

5- (5-fluoro-1-methylindol-3-yl) -4- [5-fluoro-1- (3-morpholin-4-yl-propyl) -indole-3-yl] -2,4-dihydro [ 1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 26.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.95 (1H, s); 9.96 (1H, bs); 7.86 (1H, s); 7.77 (1H, dd); 7.74 (1H, dd); 7.50 (1H, dd); 7.16 (2H, dt); 7.13 (1H, dt); 7.07 (1H, dd); 6.78 (1H, s); 4.38 (2H, t); 3.99 (2H, d); 3.67 (2H, t); 3.61 (3H, s); 3.45 (2H, d); 3.24-3.14 (2H, m); 3.14-3.00 (2H, m); 2.31-2.18 (2H, m).
APCI MS m / z: 493 [MH +].

Example 52

5- (5-fluoro-1-methylindol-3-yl) -4- {5-fluoro-1- [3- (4-methylpiperazin-1-yl) propyl] indol-3-yl} -2, 4-dihydro- [1,2,4] triazol-3-on bistrifluoroacetate

The title compound was prepared in analogy to Example 26 starting from the product of Example 18 and 1-methylpiperazine.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.95 (1H, s); 7.83 (1H, s); 7.77-7.73 (2H, m); 7.49 (1H, dd); 7, 16-7, 10 (2H, m); 7.05 (1H, dd); 6.74 (1H, s); 4.36 (2H, t); 3.60 (3H, s); 2.80 (3H, s); 2-5 ppm (12 H, broad signals).
APCI MS m / z: 506 [MH +].

Example 53

N '- (3- {5-chloro-3- [3- (5-chloro-1-methylindole-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazole 4-yl] -indole-1-yl} propyl) -N, N-dimethylimidoformamid trifluoroacetate (Compound A) and

3- {5-chloro-3- [3- (5-chloro-1-methylindole-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl] indol-1-yl} propylformamide (Compound B)

a) 3- {5-Chloro-3 - [({2 - [(5-chloro-1-methylindol-3-yl) carbonyl] hydrazino} carbonyl) amino] -indol-1-yl} -propylcarbamic acid tert. butyl ester

The sub-title compound was prepared analogously to Example 11f) starting from tert-butyl [3- (3-azidocarbonyl-5-chloroindol-1-yl) propyl] -carbamate and 5-chloro-1-methylindole-3-carbohydrazide, which were prepared in analogy to the synthesis of Example 44c) or Example 11e).
¹ H-NMR (300 MHz, acetone-d ₆ ): δ 9.36 (1H, bs); 8.33 (1H, bs); 8.24 (1H, d); 8.09 (1H, s); 7.64 (1H, bs); 7.62 (1H, d); 7.59 (1H, s); 7.40 (1H, d); 7.37 (1H, d); 7.18 (1H, dd); 7.09 (1H, dd); 4.20 (2H, t); 3.84 (3H, s); 3.11-3.06 (2H, m); 1.98 (2H, p); 1.38 (9H, s).
APCI MS m / z: 517 [MH ⁺ - ^t Bu] and 473 [MH ⁺ - Boc].

A Mixture of compound a) (180 mg, 0.34 mmol), trimethylsilyl triflate (307 μl, 1.7 mmol), triethylamine (236 μl, 1.7 mmol) and dry DMF (3 ml) was heated at 130 ° C for 1 h. The raw material obtained after evaporation consisted of two compounds. The two compounds were prepared by RP-HPLC separated from acetonitrile / water with 0.1% TFA as the mobile phase, after which the appropriate fractions were lyophilized, which the Title Compound A (118 mg, 55%) in the form of a crystallized oil and the Title compound B (45 mg, 27%) as a solid.

Title compound A

• ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 12.01 (1H, s); 9.02 (1H, dt); 8.08 (1H, d); 8.03 (1H, d); 7.87 (1H, s); 7.75 (1H, d); 7.53 (1H, d); 7.36 (1H, d); 7.30 (2H, dt); 6.77 (1H, s); 4.36 (2H, t); 3.61 (3H, s); 3.38-3.30 (2H, m); 3.14 (3H, s); 2.97 (3H, s); 2,12 (2H, p). APCI-MS m / z: 510 and 512 [MH +].

Title compound B

• ¹ H-NMR (300 MHz, DMSO-d ₆ ): δ 11.98 (1H, s); 8.14 (1H, bt); 8,10 (1H, d); 8.05 (1H, s); 7.85 (1H, s); 7.72 (1H, d); 7.51 (1H, d); 7.32 (1H, d); 7.27 (2H, dd); 6.75 (1H, s); 4.31 (2H, t); 3.60 (3H, s); 3.13-3.08 (2H, m); 1.98 (2H, p). APCI-MS m / z: 483 and 485 [MH +].

Example 54

N '- (3- {5-fluoro-3- [3- (4-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazole 4-yl] indol-1-yl} propyl) -N, N-dimethylimidoformamide trifluoroacetate (Compound A) and

3- {5-fluoro-3- [3- (4-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl] -indol-1-yl} propylformamide (Compound B)

Compound A and Compound B were prepared as for the compounds described in Example 53.
Compound A: APCI-MS: 478.2 [MH ⁺ ]
Compound B: APCI-MS: 451.1 [MH ⁺ ]

Example 55 4- [1- (3-Aminopropyl) -5-chloroindol-3-yl] -5- (5-chloro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4 ] triazol-3-one trifluoroacetate

Compound A of Example 53 was stirred in 1 M sodium hydroxide (2 ml) at 100 ° C for 2 hours. Upon addition of trifluoroacetic acid, the crude product was purified by HPLC to give the title compound (56mg, 98%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.99 (1H, s); 8.09 (1H, d); 7.84 (1H, s); 7.78 (3H, bs); 7.77 (1H, d); 7.53 (1H, d); 7.35 (1H, d); 7.31 (1H, dd); 7.28 (1H, dd); 6.72 (1H, s); 4.39 (2H, t); 3.61 (3H, s); 2.86-2.77 (2H, m); 2, 09 (2H, p).
APCI-MS m / z: 455 and 457 [MH +].

Example 56

4- [1- (3-aminopropyl) -6-fluoro-indol-3-yl] -5- (6-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (1H, s); 8.10 (1H, dd); 7.83 (3H, bs); 7.78 (1H, s); 7.64 (1H, dd); 7.36 (1H, dd); 7.26 (1H, dd); 7.04 (1H, dt); 6.95 (1H, dt); 6.63 (1H, s); 4.36 (2H, t); 3.53 (3H, s); 2.88-2.78 (2H, m); 2, 11 (2H, p).
APCI MS m / z: 423 [MH +].

Example 57

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (9H-pyrido [3,4-b] indol-3-yl) -2,4-dihydro- [1,2 , 4] triazol-3-on bistrifluoroacetate

a) 3- [3 - ({[2- (9H- (3-Carbolin-3-ylcarbonyl) hydrazino] carbonyl} amino) -5-fluoro-1-indol-1-yl] propylcarbamic acid 1,1-dimethylethyl ester

Compound 45d) (108mg, 0.30mmol) was added in toluene (3ml) to a solution of 9H- (3-carboline-3-carboxylic acid hydrazide (68mg, 0.30mmol, prepared in analogy to that described in U.S. Pat Synthesis of compound 45 b) in THF (15 ml). The mixture was stirred at room temperature overnight and concentrated. The crude material (153 mg, 91%) was used in the next step without further purification.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.02 (1H, bs); 10.21 (1H, bs); 8.96 (1H, s); 8.91 (1H, s); 8.62 (1H, bs); 8.45 (1H, d); 8.13 (1H, bs); 7.69 (1H, d); 7.63 (1H, dt); 7.56 (1H, s); 7.46 (1H, dd); 7.36-7.31 (2H, m); 7.00 (1H, dt); 6.96 (1H, bs); 4,15 (2H, t); 2.95-2.90 (2H, m); 1.84 (2H, p); 1.39 (9H, s).
APCI-MS m / z: 560 [MH +].

b) (3- {3- [3- (9H- (3-Carbolin-3-yl) -5-oxo-l, 5-dihydro- (1,2,4] triazol-4-yl] -5- fluoro-indol-1-yl} -propyl) carbamic acid tert-butyl ester

A suspension of a) (75 mg, 0.135 mmol), N, O-bis (trimethylsilyl) trifluoroacetamide (360 μl, 1.35 mmol) and N, N-diisopropylethylamine (115 μl, 0.675 mmol) in dry xylene (3 ml ) was stirred in a closed vial overnight at 130 ° C. Evaporation of the mixture gave the crude subtitle compound which was used in the next step without further purification.
APCI MS m / z: 542 [MH +].

The crude product from b) was dissolved in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (4 ml). The solution was stirred for 1 hour and then concentrated in vacuo. The crude material was purified by HPLC and lyophilized to give the title compound (53 mg, 58%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.17 (1H, s); 11.78 (1H, s); 8.61 (2H, s); 8.30 (1H, d); 7.74 (3H, bs); 7.69 (1H, s); 7.56-7.64 (3H, m); 7.30 (1H, dt); 7.03 (1H, dt); 6.92 (1H, dd); 4.30 (2H, t); 2.74-2.81 (2H, m); 2,03 (2H, p).
APCI-MS m / z: 442 [MH +].

Example 58

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5-naphthalen-1-yl-2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 57 starting from 45 d) and naphthalene-1-carboxylic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.28 (1H, s); 8.11-8.08 (1H, m); 7.96 (1H, d); 7.93-7.90 (1H, m); 7.69 (3H, bs); 7.62 (1H, dd); 7.59 (1H, s); 7.55-7.43 (4H, m); 7.08 (1H, dd); 6.98 (1H, dt); 4,15 (2H, t); 2.69-2.54 (2H, m); 1, 87 (2H, p).
APCI-MS m / z: 402 [MH +].

Example 59

5- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -4-naphthalen-1-yl-2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate a) [3- (5-Fluoro-3-hydrazinocarbonylindol-1-yl) -propyl] -carbamic acid tert-butyl ester

Caution: It will be 1 eq. Hydrazinium azide formed! The subtitle compound was prepared starting from 45 c) (362 mg, 1 mmol) in THF (10 ml) and hydrazine hydrate (100 μl, 2 mmol). The mixture was stirred for 2 hours at room temperature, diluted with water and extracted with a few portions of ethyl acetate. The combined organic phases were dried and concentrated to give the sub-title compound (332 mg, 95%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 9.16 (1H, bs); 8.05 (1H, bs); 7.82 (1H, dd); 7.56 (1H, dd); 7.07 (1H, dt); 6.96 (1H, dt); 4.34 (2H, bs); 4.21 (3H, t); 2,90-2,95 (2H, m); 1.89 (2H, p); 1.40 (9H, s).
APCI-MS m / z: 351 [MH +].

The title compound was prepared in analogy to Example 57 starting from compound a) and 1-Isocyanatonahphthalen.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.16 (1H, s); 8.22-8.18 (1H, m); 8,12 (1H, d); 7.80 (1H, dd); 7.71-7.69 (1H, m); 7.70 (1H, s); 7.65-7.58 (3H, m); 7.56 (2H, d); 7.55 (1H, dd); 7.14 (1H, dt); 6.28 (1H, s); 4.03-3.90 (2H, m); 2.49-2.39 (2H, m); 1.68 (2H, p).
APCI-MS m / z: 402 [MH +].

Example 60

5- (5-fluoro-1-methylindol-3-yl) -4- {5-fluoro-1- [2- (4-methylpiperazin-1-yl) ethyl] indol-3-yl} -2, 4-dihydro- [1,2,4] triazol-3-on bistrifluoroacetate

a) 4- [5-Fluoro-1- (2-hydroxyethyl) indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2 , 4] trazol-3-one

The sub-title compound was prepared in analogy to Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ): 12.92 (1H, s); 8.86 (1H, dd, J 10.1 and 2.6 Hz); 8.81 (1H, s); 8.72 (1H, dd, J 9.1 and 4.3 Hz); 8.50 (1H, dd, J 8.4 and 4.5 Hz); 8.15 (1H, dd, J 9.0 and 2.4 Hz); 8.10 (1H, dd, J 9.0 and 2.1 Hz); 8.04 (1H, dd, J 9.3 and 2.4 Hz); 7.80 (1H, s); 6.03 (1H, t, J 5.3 Hz); 5.38 (2H, t, J 5.3 Hz); 4.83 (2H, q, J 5.2 Hz); 4.60 (3H, s).
MS-APCI +: 410.2 [MH +].

b) Methanesulfonic acid 2- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro [1,2,4] triazole-4 -yl] -indol-1-yl} ethyl ester

The subtitle compound a) (82 mg, 0.2 mmol), methanesulfonic anhydride (38 mg, 0.22 mmol) and pyridine (0.5 mL) were stirred in dry dichloromethane (25 mL) overnight at ambient temperature. Then the solution was washed with water, dried and concentrated to give the sub-title compound (47 mg, 48%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.93 (1H, s); 7.87 (1H, s); 7.86 (1H, d); 7.76 (1H, dd); 7.49 (1H, dd); 7.19-7.09 (2H, m); 7.02 (1H, d); 6.71 (1H, s); 4.58-4.71 (4H, m); 3.56 (3H, s); 3.07 (3H, s).
APCI-MS m / z: 488 [MH +].

Compound b) (40 mg, 82 μmol) and 1-methylpiperazine (0.1 mL, 0.8 mmol) were heated in ethanol (4 mL) at 80 ° C overnight. After addition of trifluoroacetic acid, the mixture was concentrated. The residue was purified by HPLC and lyophilized to give the title compound (35mg, 59%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.94 (1H, s); 7.84 (1H, s); 7.77 (1H, dd); 7.73 (1H, dd); 7.49 (1H, dd); 7,12 (2H, dt); 7.02 (1H, dd); 6.73 (1H, s); 4.40 (2H, t); 3.59 (3H, s); 3.42-3.30 (2H, m); 3,12-2,88 (4H, m); 2.83 (2H, t); 2.76 (3H, s); 2.47-2.34 (2H, m). APCI-MS m / z: 492 [MH +].

Example 61

4- [1- (3-dimethylaminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

The title compound was prepared in analogy to Example 25 starting from the product of Example 18 and dimethylamine in ethanol.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.95 (1H, s); 10.40 (1H, bs); 7.87 (1H, s); 7.79-7.75 (2H, m); 7.50 (1H, dd); 7.15 (1H, dt); 7,12 (1H, dt); 7.06 (1H, dd); 6.78 (1H, s); 4.40 (2H, t); 3.62 (3H, s); 3.11-3.04 (2H, m); 2.74 (6H, s); 2.23 (2H, p).
APCI MS m / z: 451 [MH +].

Example 62

4- [1- (3-ethylaminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

The title compound was prepared in analogy to Example 25 starting from the product of Example 18 and ethylamine in methanol.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.95 (1H, s); 8.69 (2H, bs); 7.88 (1H, s); 7.79-7.75 (2H, m); 7.50 (1H, dd); 7.15 (1H, dt); 7,12 (1H, dt); 7.06 (1H, dd); 6.75 (1H, s); 4,43 (2H, t); 3.61 (3H, s); 2.92 (2H, g); 2.93-2.89 (2H, m); 2.17 (2H, p); 1.19 (3H, t).
APCI MS m / z: 451 [MH +].

Example 63

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (6-benzyloxy-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 45. The resulting crude product was refluxed overnight in a mixture of ethanol (10 ml) and 1 M sodium hydroxide (10 ml) overnight. After addition of trifluoroacetic acid, the mixture was evaporated. The residue was purified by HPLC and lyophilized to give the title compound (220mg, 50%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.90 (1H, s); 7.98 (1H, d); 7.83 (1H, s); 7.79 (3H, bs); 7.75 (1H, dd); 7.51-7.48 (2H, m); 7.43-7.40 (2H, m); 7.38-7.32 (1H, m); 7.16 (1H, dt); 7.12 (1H, d); 7.04 (1H, dd); 6.90 (1H, dd); 6.50 (1H, s); 5.15 (2H, s); 4.39 (2H, t); 3.52 (3H, s); 2.86-2.78 (2H, m); 2,11 (2H, p).
APCI MS m / z: 511 [MH +].

Example 64

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (6-hydroxy-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The compound (176 mg, 0.28 mmol) obtained in Example 63 was dissolved in methanol (100 ml) and added with palladium (10 wt% on charcoal, 200 mg). The mixture was hydrogenated psi overnight at ambient temperature and 60, filtered through Celite ^® and concentrated in vacuo. The residue was purified by HPLC and lyophilized to give the title compound (104mg, 69%).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.86 (1H, s); 9.29 (1H, bs); 7.89 (1H, d); 7.82 (1H, s); 7.80 (3H, bs); 7.75 (1H, dd); 7.15 (1H, dt); 7.03 (1H, dd); 6.68-6.73 (2H, m); 6.39 (1H, s); 4.39 (2H, t); 3.44 (3H, s); 2.86-2.78 (2H, m); 2, 11 (2H, p).
APCI-MS m / z: 421 [MH +].

Example 65

4- [1- (3-aminopropyl) -7-bromoindole-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11 starting from 7-bromoindole.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.00 (1H, s); 7.86 (1H, s); 7.79 (1H, dd, J 9.0 and 2.5 Hz); 7.74 (3H, bs); 7.51 (1H, dd); 7.50 (1H, d, J 8.2 Hz); 7.29 (1H, d, J 7, 6 Hz); 7, 14 (1H, dt, J 9, 2 and 2.7 Hz); 7, 01 (1H, t, J 7.7 Hz); 6.74 (1H, s); 4.69 (2H, t, J 6.4 Hz); 3.61 (3H, s); 2.88-2.79 (2H, m); 2.22-2.13 (2H, m).
APCI-MS m / z: 483 [MH +].

Example 66

4- [1- (3-Aminomethyl-benzyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

a) 3- (5-Fluoroindol-1-ylmethyl) -benzylamine

A solution of 5-fluoroindole (150 mg, 1.11 mmol) in dry DMF (3 mL) with sodium hydride (55% dispersion in oil, 63 mg, 1.44 mmol). The mixture was stirred under nitrogen for 15 min, with 2- (3-bromomethylbenzyl) isoindole-1,3-dione (403 mg, 1.22 mmol) and overnight at room temperature touched. After cooling became aqueous methylamine (40%, 5 ml) was added and the mixture heated at 80 ° C overnight. After addition of ethyl acetate the organic phase was washed three times with water and brine, dried and concentrated, giving 312 mg of the sub-title compound revealed that one for the next Step had sufficient purity.

b) tert-butyl 3- (5-fluoroindol-1-ylmethyl) benzyl] carbamate

A stirred solution of crude a) (0.31 g, 1.11 mmol) in THF (17 mL) was treated with di-tert-butyl dicarbonate (247 mg, 1.13 mmol) followed by caustic soda (1 M, 1, 7 ml) and water (3.3 ml). After 30 min, the THF was evaporated and ethyl acetate (15 ml) and water (15 ml) added. The aqueous phase was extracted with ethyl acetate, after which the combined organic phases were washed twice with water and brine, dried and concentrated. The residue was purified by flash chromatography to give 231 mg (59%) of the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): δ 7.31 to 6.87 (8H, m); 6.51 (1H, d, J 3.0 Hz); 5.29 (2H, s); 4.80 (1H, bs); 4.26 (2H, s); 1.45 (9H, s).

c) 1- [3- (tert-butoxycarbonylaminomethylbenzyl) -5-fluoroindole-3-carboxylic acid

To a solution of compound b) (100 mg, 0.28 mmol) in dioxane (1 mL) was added trichloroacetyl chloride (157 μL, 1.41 mmol) and pyridine (228 μL, 2.82 mmol). The mixture was heated to 80 ° C for 2.5 h and then poured onto ice. After addition of ethyl acetate, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed three times with water and brine, dried and concentrated. The residue was dissolved with methanol (1 ml). After addition of sodium hydroxide solution (25%, 2.5 ml), the mixture was heated to 90 ° C for 2.5 h. After cooling, the mixture was acidified by addition of 1 M hydrochloric acid. The aqueous solution was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated to give 119 mg of the sub-title compound which had sufficient purity for the next step.
APCI-MS m / z: 299 [MH +] - t-Boc.

d) [3- (3-Azidocarbonyl-5-fluoroindol-1-ylmethyl) benzyl] carbamic acid tert-butyl ester

The sub-title compound was prepared from compound d) in analogy to Example 1.
¹ H-NMR (400 MHz, CDCl ₃ ): δ 7.93 (1H, dd, J 9.4 and 2.5 Hz); 7.87 (1H, s); 7.35-6.98 (6H, m); 5.31 (2H, s); 4.84 (1H, bs); 4.29 (2H, s); 1.45 (9H, s).

e) 4- [1- (3-tert-Butoxycarbonylaminomethylbenzyl) -5-fluoro-1H-indol-3-yl] -1- (1-methylindole-3-carbonyl) semicarbazide

Compound d) was refluxed in dry toluene (1.5 ml) for 1 h. After cooling to room temperature, this solution was added to a mixture of Example 11e) (42 mg, 0.205 mmol) in dry THF (12 mL) and stirred overnight. Concentration of the mixture gave the crude subtitle compound.
APCI-MS m / z: 502 [MH +] - t-Boc.

Compound e) (0.205 mmol) was treated with N, O-bis (trimethylsilyl) trifluoroacetamide (0.47 mL, 1.78 mL) and N, N -diisopropylethylamine (0.20 mL, 1.17 mmol) in xylene (2 ml). The mixture was heated at 140 ° C for 4 hours and then evaporated. The residue was dissolved in hydrochloric acid (3 M in ethyl acetate), stirred for 2 hours and freed from the solvents in vacuo. The residue was purified by preparative HPLC and lyophilized to give 23 mg (19%) of the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.97 (1H, s); 8.15 (3H, bs); 7.93 (1H, s); 7.75 (1H, dd, J 10.0 and 2.6 Hz); 7.65 (1H, dd, J 9.5 and 4.4 Hz); 7.53 (1H, s); 7.50 (1H, dd, J 9.1 and 4.5 Hz); 7.46-7.40 (2H, m); 7.23 (1H, d); 7.16-7.06 (3H, m); 6.75 (1H, s); 5.53 (2H, s); 4.04 (2H, q, J 5.9 Hz); 3.57 (3H, s).
APCI MS m / z: 485 [MH +].

Example 67

4- [1- (3-aminopropyl) -5-methoxyindol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 66. [3- (3-Azidocarbonyl-5-methoxyindol-1-yl) -propyl] -carbamic acid tert-butyl ester was prepared as described in Example 44c) starting from 5-methoxyindole.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.90 (1H, s); 8.11 (1H, d, J 7.8 Hz); 7.82 (3H, bs); 7.69 (1H, s); 7.61 (1H, d, J 9.0 Hz); 7.46 (1H, d, J 8.2 Hz); 7.25 (1H, dt, J 7.6 and 1.3 Hz); 7.17 (1H, dt, J 7.5 and 1.2 Hz); 6.91 (1H, dd, J 8.9 and 2.4 Hz); 6.68 (1H, d, J 2.3 Hz); 6.63 (1H, s); 4.35 (2H, t, J 6.8 Hz); 3.64 (3H, s); 3.57 (3H, s); 2.85-2.75 (2H, m); 2.15-2.05 (2H, m). APCI-MS m / z: 417.1 [MH +].

Example 68

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (6-chloro-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 66 starting from 45 c) and 6-chloro-1-methylindole-3-carboxylic acid hydrazide. The hydrazide was prepared as described in the synthesis of Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (1H, s); 8.09 (1H, d, J 8.4 Hz); 7.84 (1H, s); 7.81 (3H, bs); 7.75 (1H, dd, J 9.2 and 4.2 Hz); 7.63 (1H, d, J 1.5 Hz); 7.20 (1H, dd, J 8.6 and 1.9 Hz); 7.15 (1H, dt, J 9.2 and 2.3 Hz); 7.06 (1H, dd, J 9.3 and 2.3 Hz); 6.68 (1H, s); 4.39 (2H, t, J 6.8 Hz); 3.58 (3H, s); 2.86-2.77 (2H, m); 2.16-2.06 (2H, m).
APCI-MS m / z: 439 [MH +].

Example 69

4- (8-amino-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl) -5- (5-fluoro-1-methylindol-3-yl) -2,4- dihydro [1,2,4] triazol-3-one trifluoroacetate

a) (10-Chlorocarbonyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-8-yl) -carbamic acid tert-butyl ester

A solution of tert-butyl (6,7,8,9-tetrahydropyrido [1,2-a] indol-8-yl) carbamate (400 mg, 1.40 mmol) in dry THF (5 mL) was brought to 0 ° C cooled. Then a solution of triphosgene (208 mg, 0.7 mmol) in dry THF (3 mL) and triethylamine (194 μL, 1.40 mmol) was added. It formed a precipitate. The reaction was allowed to come to room temperature and evaporated after 2 h, after which the crude product was used in the next step.
APCI-MS m / z: 345 [MH +] (Since the analysis was performed on a methanol-quenched sample, the mass corresponds to the methyl ester).

b) (10-Azidocarbonyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-8-yl) -carbamic acid tert -butyl ester

A solution of compound a) (489 mg, 1.4 mmol) in dry DMF (6 mL) was cooled to 0 ° C and sodium azide (227 mg, 3.5 mmol) was added. Then, the reaction was allowed to come to room temperature and stirred overnight. He was then poured into a mixture of ethyl acetate and water. The organic layer was separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were washed with as little water as possible and dried over sodium sulfate. The solution was evaporated and the crude mixture used in the next step.
IR: V: 2129, 8 cm ^-1 , 1666, 4 cm ^-1 .

c) 4- (8-tert-Butoxycarbonylamino-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl) -1- (5-fluoro-1-methylindole-3-carbonyl) semicarbazide

Crude compound b) was dissolved in toluene (14 ml) and heated to 110 ° C for 1.5 hours. After addition of compound 11e) (100mg, 0.48mmol) in dry THF (15ml), the mixture was stirred overnight, evaporated and used in the next step without further purification.
APCI-MS m / z: 535 [MH +].

The Title compound was prepared in analogy to Example 1 and obtained in the form of a mixture of two diastereomers. The diastereomers could be separated by HPLC, with 45 mg isomers A and 51 mg isomer B was obtained.

Isomer A

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.97 (1H, s); 8.07 (3H, bs); 7.85 (1H, dd, J 10.1 and 2.6 Hz); 7.57 (1H, d, J 8.2 Hz); 7.48 (1H, dd, J 9.0 and 4.5 Hz); 7.26 to 7.17 (2H, m); 7.16 to 7.04 (2H, m); 6.62 (1H, s); 4.56 to 4.48 (1H, m); 4.12 (1H, dt, J 12.1 and 4.8 Hz); 3.72 (1H, bs); 3.56 (3H, s); 3.19 (1H, dd, J 16.2 and 4.7 Hz); 2.63 (1H, dd, J 16.3 and 10.0 Hz); 2.45 to 2.37 (1H, m); 2.24 to 2.11 (1H, m).

Isomer B

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.98 (1H, s); 8,12 (3H, bs); 7.86 (1H, dd, J 10.2 and 2.7 Hz); 7.57 (1H, d, J 8.2 Hz); 7.47 (1H, dd, J 9.0 and 4.4 Hz); 7.22 (1H, t, J 7, 8 Hz); 7, 15 to 7, 09 (2H, m); 7, 05 (1H, t, J 7, 1 Hz); 6.73 (1H, s); 4.56 to 4.48 (1H, m); 4.16 (1H, dt, J 11.7 and 4.7 Hz); 3.68 (1H, bs); 3.55 (3H, s); 3.08 (1H, dd, J 16.3 and 5.1 Hz); 2.87 (1H, dd, J 16.2 and 10.2 Hz); 2.47 to 2.39 (1H, m); 2.23 to 2.11 (1H, m). APCI MS m / z: 417 [MH +].

The Stereoisomerism can occur with the asymmetric carbon in the 6-membered Ring next to the amino group and thus that in the ring closure step forms a form of atropisomerism. The indole on the left, with the six-membered one Ring is annealed, and the indole on the right can do not rotate freely. The rotamers transform into each other when heated around. This can easily be followed by NMR.

Example 70

4- (8-Aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl) -5- (1-methylindazol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 13 from 13a) and 1-methylindazole-3-carboxylic acid hydrazide. The product was obtained in the form of a mixture of stereoisomers (rotamers) and could be detected by NMR (see Example 69).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 12.28 (0.5H, s); 12.27 (0.5H, s); 8.07 (1H, dd, J 8.3 and 14.5 Hz); 7.86 (3H, bs); 7.62 (1H, dd, J 8.4 and 2.5 Hz); 7.48 to 7.41 (2H, m); 7.25 (1H, t, J 7.6 Hz); 7.14 to 6.92 (3H, m); 4.51 to 4.40 (1H, m); 4.00 to 3.88 (1H, dq, J 15.4 and 4.5 Hz); 3.81 (1.5H, s); 3.79 (1.5H, s); 3.07 (1H, dt, J 16.2 and 4.1 Hz); 3.01 to 2.85 (2H, m); 2.63 to 2.43 (1H, m); From 2.33 to 2.24 (1H, m); 2.24 to 2.13 (1H, m); 1.91 to 1.73 (1H, m).
APCI-MS m / z: 414 [MH +]. Example 71 4- (2-Aminomethyl-2,3-dihydropyrrolo [1,2-a] indol-9-yl) -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

a) 4- (2-azidomethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indol-9-yl) -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro- [1,2,4] triazol-3-one

The sub-title compound was prepared in analogy to Example 69 starting from Example 11e) and 2-azidomethyl-2,3-dihydro-1H-pyrrolo [1,2-a] indole-9-carbonyl azide.
APCI-MS m / z: 443 [MH +].

The title compound was prepared in analogy to Example 11 and was obtained in the form of a mixture of stereoisomers (rotamers) which could be detected by NMR (see Example 70).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.92 (1H, s); 7.95 (3H, bs); 7.81 (1H, dd, J 10.0 and 2.6 Hz); 7.48 (1H, dd, J 9.0 and 4.6 Hz); 7.43 (1H, d, J 8.2 Hz); 7.20 to 7.08 (3H, m); 7.00 (1H, bt, J 7.7 Hz); 6.79 (1H, d, J 1.9Hz); From 4.48 to 4.37 (1H, m); 4.11 (0.5H, dd, J 10.7 and 5.9 Hz); 4.03 (0.5H, dd, J 10.2 and 6.6 Hz); 3.58 (1.5H, s); 3.57 (1.5H, s); 3.35 to 3.24 (1H, m); 3.21 to 2.94 (3H, m); 2, 84 (0, 5H, dd, J 16, 7 and 7, 0 Hz); 2, 71 (0.5H, dd, J 16.3 and 5.8 Hz). APCI MS m / z: 417 [MH +].

Example 72 4- [1- (3-aminopropyl) -6-hydroxyindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4 ] triazol-3-one trifluoroacetate

a) 4- [1- (3-aminopropyl) -6-benzyloxyindol-3-yl) -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [ 1,2,4] triazol-3-one trifluoroacetate

The sub-title compound was prepared in analogy to Example 44.
APCI MS m / z: 511 [MH +].

The title compound was prepared in analogy to Example 64 starting from a).
¹ H-NMR (400 MHz, DMSO-d ₆ ): 11.88 (1H, s); 9.30 (1H, s); 7.83 to 7.70 (4H, m); From 7.52 to 7.45 (2H, m); 7.10 (1H, bt, J 8.4 Hz); 7.01 (1H, d, J 8.4 Hz); 6.96 (1H, s); 6.66-6.59 (2H, m); 4.23 (2H, t, J 6.7 Hz); 3.56 (3H, s); 2, 80 (2H, m); 2, 06 (2H, m).
APCI-MS m / z: 421 [MH +].

Example 73

4- [1- (3-aminopropyl) -6-fluoro-indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 11.
¹ H-NMR (400 MHz, acetone-d ₆ ): δ 10.99 (1H, bs); 8.25 (1H, d, J 8.0 Hz); 7.56 (1H, s); From 7.31 to 7.39 (3H, m); 7.23 (1H, t, J 7.6 Hz); 7.16 (1H, t, J 7.0 Hz); 6.87 (1H, dt, J 9.2 and 2.3 Hz); 6.68 (1H, s); 4.40 (2H, t, J 6.8 Hz); 3.55 (3H, s); 3.18 (2H, t, J 6.4 Hz); 2.84 (2H, bs); 2,17 (2H, m).
MS-ESI +: m / z 405.2 [MH +].

Example 74

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (3-bromophenyl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 45 starting from Example 45c) and 3-bromobenzoic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.20 (1H, s); 7.71 (1H, s); 7.63 to 7.67 (2H, m); 7.55 (1H, s); 7.32 (1H, d, J 7.9 Hz); 7.22 (1H, t, J 7.8 Hz); 7.04 to 7.11 (2H, m); 4.29 (2H, t, J 7.2 Hz); 2.71 (2H, t, J 7.4 Hz); 2.00 (2H, m).
MS-ESI +: m / z 430.1 [MH +].

Example 75

4- [1- (3-Aminopropyl) -5-fluoroindol-3-yl] -5- (4-bromophenyl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 66 starting from Example 45c) and 4-bromobenzoic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.20 (1H, s); 7.98 (2H, bs); 7.75 (1H, s); 7.75 (1H, dd, J 9.0 and 4.4 Hz); 7.50 (2H, dm, J 8.4 Hz); 7.38 (2H, dm, J 8.6 Hz); 7.06 (1H, dt, J 9.2 and 2.5 Hz); 6.99 (1H, dd, J 9.5 and 2.5 Hz); 4.32 (2H, t, J 6.7 Hz); 2.70 (2H, m); 2.02 (2H, m).
MS-LSIMS +: m / z 430.0 [MH +].

Example 76

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (3,5-dichlorophenyl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared in analogy to Example 66 starting from Example 45c) and 3,5-dichlorobenzoic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.34 (1H, s); 7.75 (1H, s); 7.66 to 7.83 (2H, m); 7.65 (1H, dd, J 9.7 and 5.3 Hz); 7.61 (1H, t, J 1.9 Hz); 7.34 (2H, d, J 1.9 Hz); 7.07 to 7.12 (2H, m); 4.31 (2H, t, J 6.9 Hz); 2.74 (2H, bs); 2.00 (2H, m).
MS-LSIMS +: m / z 420.0 [MH +].

Example 77

4- [1-1-benzyl-piperidin-4-ylmethyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1,2,4 ] triazol-3-one hydrochloride

a) 1-Benzyl-1-azoniabicyclo [2.2.1] heptane methanesulfonate

An ice-cooled solution of N-benzyl-4-hydroxymethylpiperidine (531 mg, 2.59 mmol) and N, N-diisopropylethylamine (0.66 mL, 3.88 mmol) in dichloromethane (3 mL) was added dropwise with methanesulfonyl chloride (0, 22 ml, 2.85 mmol) in dichloromethane (2 ml). The mixture was stirred for 5 min, diluted with tert-butyl methyl ether, and washed with water and brine. Removal of the solvents gave the sub-title compound.
¹ H-NMR (400 MHz, CDCl _3): δ 7.63 (2H, m); 7.41 (3H, m); 5.03 (2H, s); 3.88 (2H, m); 3.65 (2H, s); 3.40 (2H, m); 2.88 (1H, m); 2.83 (3H, s); 2.27 (2H, m); 1.73 (2H, m).

b) 1- (1-Benzylpiperidin-4-ylmethyl) -5-fluoroindole

To a stirred solution of sodium hydride (60%, 116 mg, 3.04 mmol) in DMF (2 mL) was added dropwise at 0 ° C 5-fluoroindole (391 mg, 2.89 mmol) in DMF (2 mL). After 30 minutes, a solution of compound a) (987 mg, 3.47 mmol) in DMF (6 mL) was added and the reaction mixture was stirred at 50 ° C overnight. Then the mixture was diluted with ethyl acetate, washed three times with water and dried over sodium sulfate. By evaporation of the solvent, the crude product was obtained in the form of a mixture of two constitutional isomers. Silica gel chromatography (heptane-ethyl acetate-methanol, 20: 80: 5) gave the sub-title compound (138mg, 15%) and 1- [2- (1-benzylpyrrolidin-3-yl) ethyl] -5-fluoro 1H-indole (338 mg, 36%).
Under the title compound:
¹ H-NMR (400 MHz, CDCl _3): δ 7.22 to 7.29 (6H, m); 7.20 (1H, dd, J 9.0 and 4.4 Hz); 7.07 (1H, d, J 3.0 Hz); 6.41 (1H, dd, J 3.2 and 1.8 Hz); 3.95 (2H, d, J 7.2 Hz); 3.46 (2H, s); 2.86 (2H, bd, J 11.6 Hz); 1.77 to 1.92 (4H, m); From 1.49 to 1.61 (3H, m); 1.35 (2H, m).
APCI MS: 323.2 [MH +].

1- [2- (1-Benzyl-pyrrolidin-3-yl) ethyl] -5-fluoro-1H-indole (Constitutional isomer)

• ¹ H-NMR (400 MHz, CDCl _3): δ 7.22 to 7.32 (7H, m); 7.18 (dd, J 9.0 and 3.3 Hz); 7.04 (1H, d, J 3.2 Hz); 6.93 (1H, dt, J 9.0 and 2.5 Hz); 6.40 (1H, dd, J 3.1 and 0.6 Hz); 4.06 (2H, m); 3.57 (2H, J 12.8 Hz); 2.73 (1H, m); 2.63 (1H, m); 2.49 (1H, m); 2.17 to 1.81 (5H, m); 1.42 (1H, m). APCI MS: 323.2 [MH +].

c) [1- (1-Benzylpiperidin-4-ylmethyl) -5-fluoroindol-3-yl] -2,2,2-trichloro-ethanone

To a solution of subtitled compound b) (138 mg, 428 μmol) in dichloromethane (3 ml) was added pyridine (40 μl, 471 μmol) and trichloroacetyl chloride (0.14 ml, 1.28 mmol) at room temperature. The reaction mixture was stirred overnight and diluted with ethyl acetate. Then, the mixture was washed with water and saturated aqueous sodium hydrogencarbonate and dried over sodium sulfate. Purification by silica gel chromatography (heptane-ethyl acetate-methanol, 50: 50: 1 followed by 0: 100: 2) afforded the sub-title compound (336 mg, 78%).
APCI MS: 467.1, 469.0 [MH +].

d) 1- (1-Benzylpiperidin-4-ylmethyl) -5-fluoro-1H-indole-3-carboxylic acid hydrazide

Compound c) (157 mg, 336 μmol) in THF (1 ml) was treated with hydrazine hydrate (33 μl, 672 μmol). The reaction mixture was heated at 80 ° C for 3 hours, diluted with ethyl acetate, washed twice with brine and dried over sodium carbonate. Purification by silica gel chromatography (ethyl acetate-methanol-ammonia, 90: 10: 0 followed by 80: 20: 2) gave 95 mg (74%) of the sub-title compound.
APCI MS: 381.3 [MH +].

e) 1- (1-Benzylpiperidin-4-ylmethyl) -5-fluoro-1H-indole-3-carbonyl azide

Compound d) (95 mg, 250 μmol) in water / acetic acid (1: 1.1 ml) was treated at 0 ° C. with a solution of sodium nitrite (34 mg, 499 μmol) in as little water as possible. The reaction mixture was diluted with water and ethyl acetate after about 2 minutes and neutralized with sodium carbonate. The organic layer was separated, washed with water and dried over sodium sulfate. Evaporation of the solvent gave 100 mg of the sub-title compound in quantitative yield.
IR: V: 2132 (vs), 1673 (s).

The title compound was prepared in analogy to Example 1 starting from the subtitle compound e) and the product from Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 10, 14 (1H, bs); 7.72 (1H, s); 7.65 (1H, dd, J 9.0 and 4.2 Hz); 7.60 (1H, dd, J 10.1 and 4.5 Hz); 7.50 to 7.52 (2H, m); 7.43 to 7.45 (3H, m); 7.41 (1H, dd, J 9.0 and 4.5 Hz); 7.01 to 7.10 (3H, m); 6.82 (1H, s); 4.21 (2H, d, J 5.0 Hz); 4.14 (2H, d, J 7.1 Hz); 3.54 (3H, s); 3.28 (2H, m); 2.80 (2H, bq, J 10.6 Hz); 2.03 (1H, m); 1.47 to 1.69 (4H, m).
MS-LSIMS +: m / z 553.3 [MH +].

Example 78

5- (5-fluoro-1-methylindol-3-yl) -4- (5-fluoro-1-piperidin-4-ylmethylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

The title compound from Example 77 was hydrogenated in acetic acid / methanol (1: 1) with palladium on carbon (10%) for 24 h at 50 psi to give the title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 8.51 (1H, bs); 8.23 (1H, bs); 7.75 (1H, s); 7.65 to 7.71 (2H, m); 7.45 (1H, dd, J 9.0 and 4.5 Hz); 7.02 to 7.12 (3H, m); 6.75 (1H, s); 4.17 (2H, d, J 7.3 Hz); 3.56 (3H, s); 3.25 (2H, bd, J 12.5 Hz); 2.80 (2H, bq, J 10.3 Hz); 2,12 (1H, m); 1.62 (2H, bd, J 12.4 Hz); 1.36 (2H, bq, J 12.0 Hz).
MS-LSIMS +: m / z 463.1 [MH +].

Example 79

4- [1- (1-Benzyl-4-ylmethyl) indol-3-yl] -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one hydrochloride

The title compound was prepared in analogy to Example 77. In the synthesis of the title compound, a constitutional isomer was also obtained as an intermediate (see Example 77). This was used for the synthesis of Example 81.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 8.04 (1H, bd, J 8.0 Hz); 7.66 (1H, s); 7.64 (1H, bs); 7.39 (1H, d, J 8.4 Hz); 7.18 to 7.36 (8H, m); 7.10 (1H, t, J 7.8 Hz); 7.04 (1H, t, J 8.3 Hz); 6.62 (1H, bs); 4.16 (2H, d, J 6.8 Hz); 3.43 (2H, bs); 3.32 (3H, s); 2.79 (2H, m); 1.85 (3H, m); 1.45 (2H, m); 1.29 (2H, m).
MS-LSIMS +: m / z 517.3 [MH +].

Example 80

5- (1-methylindole-3-yl) -4- (1-piperidin-4-ylmethylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

The title compound was prepared analogously to Example 78 starting from the title compound from Example 79.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.90 (1H, s); 8.48 (1H, bs); 8.18 (1H, bs); 8.04 (1H, d, J 7.6 Hz); 7.70 (1H, s); 7.67 (1H, d, J 8.5 Hz); 7.43 (1H, d, J 8.2 Hz); 7.20 to 7.27 (3H, m); 7.13 (1H, t, J 7.4 Hz); 7.06 (1H, t, J 7.5 Hz); 6.67 (1H, s); 4.20 (2H, s); 3.54 (3H, s); 3.31 (2H, m); 2.83 (2H, bq, J 11.4 Hz); 2.17 (1H, bs); 1.66 (2H, bd, J 11.8 Hz); 1.39 (2H, bq, J 11.3 Hz).
MS-LSIMS +: m / z 427.1 [MH +].

Example 81

4- {1- [2- (1-Benzyl-pyrrolidin-3-yl) ethyl] indol-3-yl} -5- (1-methylindol-3-yl) -2,4-dihydro- [1,2 , 4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 77 starting from the constitutional isomer obtained in the synthesis of the title compound according to Example 79.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 8.09 (1H, d, J 8.0 Hz); 7.72 (1H, s); 7.60 (1H, d, J 8.6 Hz); 7.41 (1H, d, J 8.2 Hz); 7.20 to 7.25 (8H, m); 7.13 (1H, t, J 7.5 Hz); 7.04 (1H, t, J 7.7 Hz); 6.59 (1H, s); 4.25 (2H, t, J 6.8 Hz); 3.54 (1H, bs); 3.50 (3H, s); 3.32 (2H, s); 2.70 (1H, m); 2.40 (1H, bs); 2.14 (1H, bs); From 1.82 to 1.99 (4H, m); 1.43 (1H, m).
MS-LSIMS +: m / z 517.3 [MH +].

Example 82

5- (1-methylindole-3-yl) -4- [1- (2-pyrrolidin-3-yl-ethyl) -indole-3-yl] -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

The title compound was prepared analogously to Example 78 starting from the title compound according to Example 81.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.89 (1H, s); 8.06 (1H, d, J 8.0 Hz); 7.72 (1H, s); 7.63 (1H, d, J 8.6 Hz); 7.40 (1H, d, J 8.2 Hz); 7.19 to 7.23 (3H, m); 7.12 (1H, t, J 7.5 Hz); 7.02 (1H, t, J 7.4 Hz); 6.59 (1H, s); 4.27 (2H, t, J 6.8 Hz); 3.50 (3H, s); 3.04 (1H, m); 2.95 (1H, m); 2.84 (1H, m); 2.51 (1H, m); From 1.84 to 1.97 (5H, m); 1.39 (1H, m).
MS-ESI +: m / z 427.1 [MH +].

Example 83

1- (3-dimethylaminopropyl) -3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl] indole-5-carbonsäuremethylester hydrochloride

The title compound was prepared in analogy to Example 11 starting from 3-azidocarbonyl-1- (3-dimethylaminopropyl) -1H-indole-5-carboxylic acid methyl ester and the product from Example 11e).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.98 (1H, s); 7.88 (1H, dd, J 15.5 and 2.7 Hz); 7.84 (2H, s); 7.76 (1H, d, 8.8 Hz); 7.70 (1H, dd, J 10.1 and 2.7 Hz); 7.46 (1H, dd, J 9.0 and 4.4 Hz); 7.09 (1H, dt, J 9.2 and 2.7 Hz); 6.71 (1H, s); 4.32 (2H, t, J 6.8 Hz); 3.56 (3H, s); 3.79 (3H, s); 2.13 (2H, t, J 6.9 Hz); 2.08 (6H, s); 1.92 (2H, m).
MS-LSIMS +: m / z 491.0 [MH +].

Example 84

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-methyl-6-trifluoromethylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

The title compound was prepared in analogy to Example 11 starting from 1,6-dimethylindole-3-carboxylic acid hydrazide and the product from Example 11d).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.99 (1H, s); 8.22 (1H, d, J 8.3 Hz); 7.88 (1H, s); 7.70 (5H, m); 7.44 (1H, dd, J 9.5 and 1.3 Hz); 7.10 (1H, td, J 9.1 and 2.5 Hz); 7.02 (1H, dd, J 9.1 and 2.5 Hz); 6.83 (1H, s); 4.34 (2H, t, J 6.7 Hz); 3.65 (3H, s); 2.77 (2H, bs); 2.03 (2H, m).
MS-LSIMS +: m / z 473.1 [MH +], 474.1 [MH ₂ +].

Example 85

3- {4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5-oxo-4,5-dihydro [1,2,4] triazol-3-yl} -1-methylindole 5-carbonitrile trifluoroacetate

The title compound was prepared in analogy to Example 11 starting from 5-cyano-1-methylindole-3-carboxylic acid hydrazide and the product from Example 11d).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.03 (1H, s); 8.41 (1H, d, J 1.5 Hz); 7.79 (1H, s); 7.65 (4H, m); 7.59 (1H, dd, J 8.6 and 1.7 Hz); 7.11 (1H, dt, J 7.2 and 2.5 Hz); 7.05 (1H, dd, J 7.3 and 2.5 Hz); 6.83 (1H, s); 4.33 (2H, t, J 6.8 Hz); 3.62 (3H, s); 2.76 (2H, m); 2.03 (2H, m).
MS-LSIMS +: m / z 430.2 [MH +].

Example 86

4- {1- [3- (4-Benzyl-piperazin-1-yl) propyl] -5-fluoro-indol-3-yl} -5- (5-fluoro-1-methylindol-3-yl) -2,4- dihydro- [1,2,4] triazol-3-one dihydrochloride

The title compound was prepared in analogy to Example 26 from that of the product of Example 18 and 1-benzylpiperazine.
¹ H-NMR (400 MHz, CDCl _3): δ 7.95 (1H, dd); 7.35 to 7.20 (8H); 7.05 (2H, m); 6.95 (2H, m); 6.15 (1H, s); 4.10 (2H, d, J 4.6 Hz); 3.30 (2H, s); 3.20 (3H, s); 2.40 to 2.25 (8H); 1.95 (2H, d, J 4.6 Hz); 1.15 (2H).
APCI-MS m / z: 582.1 [MH +].

Example 87

4- {5-fluoro-1- [3- (2-hydroxyethylamino) propyl] indol-3-yl} -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 26 starting from the product of Example 18 and 2-aminoethanol.
¹ H-NMR (400 MHz, CDCl _3): δ 7 85 (2H, m); 7.35 (2H, m); 7.30 (1H, s); 7.05 (2H, m); 6.95 (2H, m); 6.40 (1H, s); 4,10 (2H, m); 3.95 (3H, s); 3.55 (2H, m); 3.30 (2H, s); 2.55 (2H, m); 2.00 (2H, m). APCI-MS m / z: 467.1 [MH +].

Example 88

4- [1- (3-benzylamino-propyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one hydrochloride

The title compound was prepared in analogy to Example 26 and starting from the product of Example 18 and benzylamine.
¹ H-NMR (400 MHz, CDCl _3): δ 9.15 (1H, bs); 7.85 (1H, dd); 7.20 to 7.10 (8H); 7.00 (2H, m); 6.25 (1H, s); 4.40 (2H, s); 4.10 (2H, d, J 4.3 Hz); 3.25 (3H, s); 2.25 (2H, d, J 4.3 Hz); 1.55 (1H, bs); 1.05 (2H, m).
APCI MS m / z: 514.1 [MH +].

Example 89

4- {1- [3- (3,5-dimethylpiperazine-1-yl) propyl] -5-fluoro-indol-3-yl} -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro- [1,2,4] triazol-3-one dihydrochloride

The title compound was prepared analogously to Example 26 starting from the product of Example 18 and 2,6-dimethylpiperazine.
¹ H NMR (400 MHz, CD ₃ OD): δ 7.55 (1H, s); 7.45 (2H, m); 7.20 (1H, m); 7.00 (1H, m); 6.90 (2H, m); 6.65 (1H, s); 4.15 (2H, t, J 3.7 Hz); 3.65 (2H, m); 3.55 (3H, s); 3.05 (2H, t, J 3.7 Hz); 2.25 (3H, m); 1.60 (6H, s); 1.05 (2H, m).
APCI-MS m / z: 520.4 [MH +].

Example 90

4- {1- [3- (2,6-dimethylmorpholine-4-yl) propyl] -5-fluoro-indol-3-yl} -5- (5-fluoro-1-methylindol-3-yl) -2, 4-dihydro- [1,2,4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 26 starting from the product of Example 18 and 2,6-dimethylmorpholine.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.90 (1H, s); 7.85 (2H, m); 7.55 (1H, m); 7.15 (2H, m); 7.00 (1H, m); 6.80 (1H, s); 4.35 (2H, t); 3.60 (3H, s); 3.55 (2H, d); 3.15 to 3.00 (4H, m); 2.55 (2H, t); 1.15 (6H, 2s); 1.00 (2H, m).
APCI-MS m / z: 521.1 [MH +].

Example 91

5- (5-fluoro-1-methylindol-3-yl) -4- {5-fluoro-1- [4- (4-methylpiperazin-1-yl) -butyl] indol-3-yl} -2, 4-dihydro [1,2,4] triazol-3-one dihydrochloride

The title compound was prepared in analogy to Example 26 starting from the product of Example 19 and 1-methylpiperazine.
¹ H-NMR (400 MHz, CD ₃ OD): δ 7.80 (1H, s); 7.55 (2H, m); 7.20 (1H, m); 7.00 (2H, m); 6.90 (1H, m); 6.60 (1H, s); 4,15 (2H, t); 3.50-3.40 (10H, m); 3.15 (3H, s); 3.00 (3H, s); 2.25 (3H, m); 0.95 (2H, m).
APCI-MS m / z: 520.1 [MH +].

Example 92 3- {5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl ] indol-1-ylmethyl} -benzoic acid methyl ester hydrochloride

a) 3 - [(Fluoroindol-1-yl) methyl] benzonitrile

To a solution of 3 g (22.2 mmol) of 5-fluoroindole in 90 ml of dry DMF was added 8.28 g (23 mmol) of NaH and 4.51 g (23 mmol) of 3-bromomethylbenzonitrile. The mixture was stirred overnight and then partitioned between water and dichloromethane. The aqueous layer was extracted twice with dichloromethane, after which the combined organic extracts were washed with brine, dried and evaporated. The oily residue was subjected to flash chromatography using dichloromethane / hexane (1/1) as eluent to give 5.75 g (76%) of the subtitled product.
¹ H-NMR _(CDCl3): 5.30 (2H, s); 6.55 (1H, d); 6.90 (1H, tt); 7.15 (1H, q); 7,20 (1H, d); 7.30-7.40 (3H, m); 7.55 (1H, t); 7.60 (1H, dd).
APCI-MS m / z: 251.2 [MH +].

b) 3 - {[5-Fluoro-3- (2,2,2-trichloroacetyl) indol-1-yl] methyl} benzonitrile

A stirred and cooled solution of the product from a) (5.50 g, 22.2 mmol) in 120 mL of dry dioxane and pyridine (3.5 mL, 45 mmol) was added slowly through a septum with trichloroacetyl chloride (5.4 mL, 45 mmol). The resulting mixture was stirred at 80 ° C overnight, cooled and partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate, after which the combined organic phases were washed with brine, dried and evaporated. The residue was subjected to flash chromatography (ethyl acetate / hexane 1/1) to give 5.6 g (84%) of the subtitle product as an oil.
¹ H-NMR _(CDCl3): 5.45 (2H, s); 7,10 (1H, tt); 7.15 (1H, q); 7.30 (1H, d); 7.45-7.50 (2H, m); 7.60 (1H, d); 8.11 (1H, dd); 8.25 (1H, s).
APCI-MS m / z: 395.5 [MH +].

c) 1- (3-Cyanobenzyl) -5-fluoroindole-3-carboxylic acid hydrazide

To a solution of 5.5 g (14 mmol) of the product from b) in 80 ml of THF was added 1.2 ml (28 mmol) of hydrazine hydrate, after which the mixture was stirred at 50 ° C for 1 h. Upon complete reaction of the starting material, the solvent was evaporated and the residue recrystallized from TBME / MeOH to yield 2.8 g (79%) of the subtitled product.
¹ H-NMR (DMSO-d ₆ ): 8.10 (1H, s); 8.0 (1H, dd); 7.90 (1H, m); 7.70 (4H, m); 7.25 (1H, tt); 5.75 (2H, s); 4.5 (1H, bs); 3.50 (2H, bs).
APCI-MS m / z: 309.1 [MH +].

d) 1- (3-cyanobenzyl) -5-fluoroindole-3-carbonyl azide

The product from c) (2.8 g, 9 mmol) was dissolved in glacial acetic acid (30 mL) and the solution was cooled in an ice bath and then added dropwise with a solution of sodium nitrite (1.25 g, 11.8 mmol) in 20 ml of water was added, immediately causing a white solid to precipitate. After complete addition, the mixture was stirred for 30 min. And 100 ml of cold water was added and the precipitated compound was filtered off, washed with cold water and dried in vacuo overnight at room temperature, giving 2.7 g (67%) of the subtitle resulted compound.
IR: (film) 2133.1, 1669.95, 1525.25, 1466.04, 1191.71
¹ H-NMR _(CDCl3): 7.85 (1H, dd); 7.85 (1H, s); 7.60 (1H, d); 7.4 (2H, m); 7.25 (1H, d); 7.15 (1H, q); 7.0 (1H, tt); 5.5 (2H, s).

e) 3 - ({5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazole-4 -yl] -indol-1-yl} methyl) benzonitrile

The product of d) (1.36 g, 9 mmol) was dissolved in 25 ml of toluene, after which the solution was heated at 90 ° C for 6 h. After evaporation of the toluene, the crude isocyanate was dissolved in 35 ml of dry DMF and 0.86 g (9 mmol) of the hydrazide product from Example 11e) was added, after which the resulting mixture was stirred overnight. After addition of triethylamine (4.84 ml, 36 mmol), trimethylsilyl triflate (6.5 ml, 36 mmol) was added slowly, which was injected via syringe. The mixture was stirred under nitrogen overnight at 80 ° C and poured into 500 ml of ice-cold water. The precipitate formed was filtered off, washed with water and dried overnight at 40 ° C in a vacuum. Recrystallization from TBME / MeOH afforded 0.97 g (56%) of the sub-title compound.
¹ H-NMR (DMSO-d ₆ ): 7.95 (1H, s); 7.70-7.60 (5H, m); 7.50 (2H, d); 7.45 (1H, m); 7.00 (3H, m); 6.85 (1H, s); 5.55 (2H, s); 3.55 (3H, s).
APCI-MS m / z: 481.1 [MH +].

A solution of 0.96 g (0.02 mmol) of the product from e) in 25 mL of dry methanol was saturated with a gentle stream of hydrogen chloride gas with stirring and efficient cooling in an ice-salt bath and then stirred overnight at room temperature , evaporated, dissolved in methanol (20 ml) and precipitated with ethyl acetate to give the title compound as a pale yellow powder.
¹ H-NMR (DMSO-d ₆ ): 8.00 (1H, s); 7.65 (2H, m); 5.60 (1H, q); 7.50 (4H, m); 7.00 (3H, m); 6.55 (1H, s); 5.55 (2H, s); 3.50 (3H, s); 3.00 (3H, s).
APCI-MS m / z: 523.1 [MH +]. Example 93 3 - ({5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazole-4 -yl] -indol-1-yl} methyl) -N, N-dimethylbenzolcarboximidamid hydrochloride

A suspension of 90 mg (0.16 mmol) of the product of Example 92 in abs. Ethanol (5 ml) was added with 3 mmol (7 ml) of dimethylamine (40% in ethanol), after which the mixture was heated with stirring in a closed tube at 80 ° C overnight. The crude material remaining after evaporation of the volatiles was triturated with ethyl acetate. Purification by preparative HPLC (C-18 silica gel, MeCN / water with 0.1% TFA, gradient 10-90% MeCN) and lyophilization from 10 mL HCl (3N) gave the title compound.
¹ H-NMR (DMSO-d ₆ ): 12.00 (1H, s); 9.20 (1H, bs); 8.00 (1H, s); 7.75 (1H, dd); 7.55-7.45 (8H, m); 7.05 (1H, m 6.85 (1H, s); 5.55 (2H, s); 3.70 (6H, s); 3.55 (3H, s).
APCI-MS m / z: 526.1 [MH +].

Example 94

N-Benzyl-3 - ({5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-l, 5-dihydro-4H-1,2,4-triazole -4-yl] -indole-1-yl} methyl) benzenecarboximidamide hydrochloride

This compound was prepared in analogy to Example 93 starting from the product of Example 92 and 1.1 equivalents of benzylamine.
¹ H-NMR (DMSO-d ₆ ): 8.10 (1H, s); 8.05 (1H, s); 7.75 (3H, m); 7.25-7.35 (7H, m); 7,10 (4H, m); 6.85 (1H, s); 5.60 (2H, s); 4.80 (2H, s); 3.55 (3H, s). APCI-MS m / z: 588.1 [MH +].

Example 95

3 - ({5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl ] indol-1-yl} methyl) benzenecarboximidamide hydrochloride

This compound was prepared in analogy to Example 93 starting from the product in Example 92 and an excess of ammonium hydroxide.
¹ H-NMR (DMSO-d ₆ ): 10.1 (1H, bs); 8.05 (1H, s); 8.00 (1H, s); 7.70 (2H, m); 7.60-7.50 (3H, m); 7.05 (3H, m); 6.85 (1H, s); 3.55 (3H, s); 5.50 (2H, s).
APCI-MS m / z: 499.0 [MH +].

Example 96

4- (5-fluoro-1- {3- [imino (4-morpholinyl) methyl] benzyl} indol-3-yl) -5- {5-fluoro-1-methylindol-3-yl) -2,4 dihydro-3H-1,2,4-triazol-3-one hydrochloride

This compound was prepared in analogy to Example 93 starting from the product in Example 92 and 1.1 equivalents of morpholine.
¹ H-NMR (MeOD + TFA): 8.60 (1H, s); 8.55 (1H, s); 8.05 (2H, m); 7, 85 (3H, m); 7, 25 (3H, m); 7, 15 (1H, s); 5, 55 (2H, s); 4.00 (4H, m); 3.75-3.65 (4H, m); 3.50 (3H, s).
APCI-MS m / z: 569.2 [MH +].

Example 97

3 - ({5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl ] indol-1-yl} methyl) -N-isopropylbenzolcarboximidamid hydrochloride

This compound was prepared in analogy to Example 93 starting from the product in Example 92 and 1.1 equivalents of isopropyl.
¹ H-NMR (DMSO-d ₆ ): 8, 05 (1H, s); 7, 85 (2H, m); 7, 50 (3H, m); 7.45 (2H, m); 7.05 (4H, m); 6.85 (1H, s); 5.50 (2H, s); 4, 05 (1H, m); 3, 50 (3H, s); 3, 35 (3H, bs); 1, 25 (6H, d).
APCI-MS m / z: 540.1 [MH +].

Example 98

N- (3- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4 -yl] -indol-1-yl} propyl) guanidine trifluoroacetate

A solution of the product of Example 2 (0.12 g, 0.248 mmol) in absolute ethanol was treated with 1-formamidino-3,5-dimethylpyrazole (0.06 g, 0.30 mmol) and sodium bisulfate (0.05 g, 1 , 7 mmol), after which the resulting mixture was stirred overnight at 50 ° C. The crude material remaining after evaporation of the solvent was dissolved in methanol, after which the solution was acidified with TFA to a pH of about 2. The acidic solution was subjected to preparative HPLC (C-18 silica gel, MeCN / water with 0.1% TFA, gradient 10-90% MeCN). Lyophilization from water gave 37 mg of the title compound.
¹ H-NMR (CD ₃ OD): 8.10 (1H, m); 7.55 (1H, dd); 7.45 (2H, m); 7.22 (1H, m); 6.90 (2H, m); 6.60 (1H, s); 4.30 (2H, t); 3.15 (3H, s); 2,10 (2H, t); 1,10 (2H, t).
APCI MS m / z: 465.1 [MH +].

Example 99

4- {5-fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl] indol-1-yl} butanitril

To a solution of the product of Example 18 (0.86 g, 1.77 mmol) in dry DMF (25 mL) was added potassium cyanide (0.18 g, 2.77 mmol), and the mixture was stirred with stirring overnight under nitrogen was heated to 50 ° C. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The aqueous phase was washed twice with ethyl acetate, after which the combined organic phases were washed with water and dried. After evaporation, the crude product was chromatographed on silica gel (EtOAc) to give 0.46 g (61%) of the title compound.
¹ H-NMR (CD ₃ OD): 8.10 (1H, s); 7.55 (1H, m); 7.45 (1H, m); 7.11 (2H, m); 7.00 (2H, m); 6.60 (1H, s); 4.11 (3H, s); 3.55 (2H, t); 2.55 (2H, t); 2.00 (2H, m).
APCI-MS m / z: 432.1 [MH +]. Example 100 4- {5-Fluoro-3- [3- (5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro-4H-1,2,4-triazole-4 yl] -indole-1-yl} -N, N-dimethylbutanimidamid hydrochloride

A cooled and stirred suspension of the product of Example 99 in dry methanol was saturated with HCl gas. The mixture was stirred overnight and the solvent was removed, after which the residue was dried in vacuo for 3 h. This was dissolved in 10 ml of methanol and with 10 ml of dimethyl amine (40% in methanol). The mixture was heated in a closed tube with stirring overnight at 80 ° C. After cooling and evaporation, the residue was purified by preparative HPLC (C18 silica gel, acetonitrile / water with 0.1% TFA, gradient 10-90% acetonitrile). Lyophilization from water gave the title compound.
¹ H-NMR (CD ₃ OD): 8.00 (1H, s); 7.60 (1H, m); 7.50 (2H, m); 7.35 (1H, m); 7.1 (2H, m); 6.56 (1H, s); 3.55 (3H, s); 3,10 (3H, s); 3.15 (3H, s); 2.95 (2H, t); 2.55 (2H, t); 2.1 (2H, m).
APCI-MS m / z: 479.1 [MH +].

Example 101

5- (5-fluoro-1-methylindol-3-yl) -4- {1- [1- (2,2,2-trifluoroethyl) piperidin-4-yl] indole-3-yl} -2, 4-dihydro- [1,2,4] triazol-3-one

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 7.92 (1H, s); 7.77 to 7.71 (2H, m); 7.45 (1H, dd, J 9.1 and 4.5 Hz); 7.25 to 7.21 (2H, m); 7.11 to 7.03 (2H, m); 6.58 (1H, s); 4.54 (1H, m); 3.54 (3H, s); 3.32-3.24 (2H, m); 3.10 to 3.05 (2H, m); 2.77 to 2.64 (2H, m); 2.08 to 1.97 (4H, m). APCI-MS m / z: 513 [MH +].

Example 102

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5 (5-bromo-pyridin-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

The title compound was prepared in analogy to Example 45 starting from the product of Example 45d) and 5-bromonicotinic acid hydrazide.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.45 (1H, s); 8.68 (1H, d); 8.48 (1H, d); 8.00 (1H, m); 7.89 (3H, bs); 7.80 (1H, s); 7.70 (1H, m); 7.16 to 7.09 (2H, m); 4.35 (2H, m); 2.75 (2H, m); 2.04 (2H, m).
APCI-MS m / z: 431 [MH +].

Example 103

4,5-bis [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -2,4-dihydro- [1,2,4] triazol-3-one dihydrochloride

The title compound was prepared in analogy to Example 6.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.97 (1H, s); 8.07 (3H, bs); 7.92 (3H, bs); 7.86 (1H, s); 7.76 to 7.72 (2H, m); 7.61 (1H, dd, J 9.1 and 4.5 Hz); 7.15 to 7.09 (2H, m); 7.00 (1H, dd, J 9.3 and 2.4 Hz); 6.80 (1H, s); 4.41 (2H, m); 4,11 (2H, m); 2.81 (2H, m); 2.57 (2H, m); 2.12 (2H, m), 1.80 (2H, m).
APCI-MS m / z: 466 [MH +].

Example 104

4- {1- [2- (2-aminoethoxy) ethyl] -5-fluoro-indol-3-yl} -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1 , 2,4] triazol-3-one hydrochloride

The title compound was prepared essentially as described in Example 44. The final ring closure and deprotection were carried out as described for Example 66.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.97 (1H, s); 7.86 (1H, s); 7.90 to 7.66 (5H); 7.47 (1H, dd, J 8.9 and 4.5 Hz); 7.13 to 7.06 (2H, m); 7.00 (1H, dd, J 9.4 and 2.5 Hz); 6.70 (1H, s); 4.48 (2H, m); 3.80 (2H, m); 3.57 (3H, s); 3.55 (2H, m); 2.89 (2H, m).
APCI MS m / z: 453 [MH +].

Example 105

3- (3- {5-fluoro-3- [3 - (- 5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4 -yl] -indol-1-yl} propylamino) -propionic acid methyl ester hydrochloride

The title compound was prepared in analogy to Example 24.
¹ H-NMR for the amine (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 7.75 (1H, s); 7.72 (1H, dd, J 10.1 and 2.5 Hz); 7.68 (1H, dd, J 9.1 and 4.3 Hz); 7.47 (1H, dd, J 9.0 and 4.4 Hz); 7,12-7,06 (2H, m); 7.02 (1H, dd, J 9.4 and 2.5 Hz); 6.67 (1H, s); 4.30 (2H, m); 3.57 (6H, 2s); 2.68 (2H, m); 2.50 to 2.38 (4H, m); 1.90 (2H, m).
APCI-MS m / z: 509 [MH +].

Example 106

3- (3- {5-fluoro-3- [3 - (- 5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4 -yl] -indol-1-yl} propylamino) -propionic acid trifluoroacetic acid salt

The title compound (193 mg, 0.38 mmol) obtained in Example 105 was stirred in sodium hydroxide solution (25%, 13 ml) and ethanol (1.5 ml) at 90 ° C. for 1.5 h. After addition of trifluoroacetic acid, the mixture was evaporated. The residue was purified by preparative HPLC and lyophilized to give 171 mg (74%) of the title product.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12, 80 (1H, bs); 11, 94 (1H, s); 8.55 (2H, bs); 7.81 (1H, s); 7.75 (1H, dd, J 10.1 and 2.5 Hz); 7.73 (1H, dd, J 9.1 and 4.3 Hz); 7.48 (1H, dd, J 9.0 and 4.4 Hz); 7.16 to 7.07 (2H, m); 7.04 (1H, dd, J 9.3 and 2.5 Hz); 6.73 (1H, s); 4.36 (2H, m); 3.59 (3H, s); 3,12 (2H, m); 2.97 (2H, m); 2.64 (2H, m); 2.14 (2H, m).
MS-LSIMS +: m / z: 495 [MH +].

Example 107

1- (3-aminopropyl) -3- [3 - (- 5-fluoro-1-methylindol-3-yl) -5-oxo-1,5-dihydro- [1,2,4] triazol-4-yl ] -1-indole-5-carbonitrile hydrochloride

The title compound was prepared in analogy to Example 66.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.99 (1H, s); 8.05 (3H, bs); 8.01 (1H, s); 7.96 (1H, d, J 8.7 Hz); 7.91 (1H, bs); 7.75 (1H, dd, J 10.1 and 2.5 Hz); 7.65 (1H, dd, J 8.7 and 1.4 Hz); 7.48 (1H, dd, J 9.0 and 4.6 Hz); 7.10 (1H, ddd, J 11.6, 9.0 and 2.5 Hz); 6.74 (1H, s); 4.46 (2H, m); 3.60 (3H, s); 2.79 (2H, m); 2,12 (2H, m).
MS-LSIMS +: m / z: 430 [MH +].

Example 108

2- (3-aminopropyl) -4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one dihydrochloride

a) 4- [1- (3-azidopropyl) -5-fluoroindol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro- [1,2,4 ] triazol-3-one

Title compound 18 (580 mg, 1.19 mmol) and sodium azide (117 mg, 1.79 mmol) were stirred in DMF (5 mL) at 70 ° C for 0.5 h. After addition of ethyl acetate, the organic phase was washed with water and brine, dried and concentrated in vacuo. The solid residue was crystallized from ethyl acetate to give 460 mg (95%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.92 (1H, bs); 7.79 (1H, s); 7.73 to 7.67 (2H, m); 7.47 (1H, m); 7.15 to 7.01 (3H); 6.76 (1H, s); 4.33 (2H, m); 3.58 (3H, s); 2.49 (2H, m); 2.05 (2H, m).
APCI-MS m / z: 449 [MH +].

b) {3- [4- [1- (3-azidopropyl) -5-fluoroindol-3-yl] -3- (5-fluoro-1-methylindol-3-yl) -5-oxo-4,5- dihydro- [1,2,4] triazol-1-yl] -propyl} carbamic acid tert-butyl ester

Subtitle compound a) (100 mg, 0.22 mmol), tert-butyl (3-bromopropyl) carbamate (80 mg, 0.34 mmol) and potassium carbonate (61 mg, 0.44 mmol) were dissolved in DMF (2 mL ) Stirred at 70 ° C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, and concentrated in vacuo. Silica gel chromatography (ethyl acetate-toluene, 3: 1) yielded 116 mg (87%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 7.82 (1H, s); 7.77 (1H, dd, J 9.9 and 2.5 Hz); 7.70 (1H, dd, J 8.9 and 4.3 Hz); 7.48 (1H, dd, J 9.0 and 4.4 Hz); 7.15 to 7.07 (3H); 6.90 (1H, bs); 6.76 (1H, s); 4.34 (2H, m); 3.85 (2H, m); 3.59 (3H, s); 3.31 (2H, m); 3.09 (2H, m); 2.06 (2H, m); 1.94 (2H, m); 1.38 (9H, s).
APCI MS m / z: 606.5 [MH +].

c) {3- [4- [1- (3-aminopropyl) -5-fluoroindol-3-yl] -3- (5-fluoro-1-methylindol-3-yl) -5-oxo-4,5- dihydro- [1,2,4] triazol-1-yl] -propyl} carbamic acid tert-butyl ester

Subtitle compound b) (107 mg, 0.18 mmol), triphenylphosphine (232 mg, 0.88 mmol) and water (32 μl, 1.77 mmol) was stirred in THF (4 mL) overnight at room temperature. After adding aqueous ammonium hydroxide (25%, ~ 0.1 ml), the mixture was stirred for 0.5 h and concentrated in vacuo. Silica gel chromatography (dichloromethane-methanol-ammonium hydroxide, 25% in water, 100: 10: 1) gave 66 mg (65%) of the sub-title compound.
APCI MS m / z: 580 [MH +].

Subtitle compound c) was dissolved in acetonitrile / water (1: 1.5 ml). After adding hydrochloric acid (about 50 μl), the solution was stirred at 70 ° C for 0.5 hours. Then the mixture was concentrated in vacuo, dissolved in water and lyophilized.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.30 (3H, bs); 8.15 (3H, bs); 7.94 (1H, s); 7.84 (1H, dd, J 10.0 and 2.6 Hz); 7.79 (1H, dd, J 9.1 and 4.3 Hz); 7.50 (1H, dd, J 9.1 and 4.5 Hz); 7.16 to 7.09 (2H, m); 7.07 (1H, dd, J 9.3 and 2.5 Hz); 6.68 (1H, s); 4.42 (2H, m); 3.96 (2H, m); 3.60 (3H, s); 2.97 (2H, m); 2.78 (2H, m); 2,15 (4H, m).
APCI-MS m / z: 480 [MH +].

Example 109

4- [1 (S) - (3 (S) -Diethylaminocyclopentyl) -5-fluoro-indol-3-yl] -5- (5-fluoro-1-methylindol-3-yl) -2,4-dihydro [1, 2,4] triazol-3-one trifluoroacetate

The product of Example 3 (29.0 mg, 60.0 μmol) was dissolved in 1 ml of methanol and applied to a 30 ml silica column. The free base was eluted with ammonia-saturated methylene chloride-methanol (6: 1), giving after evaporation 24.6 mg (57 μmol). This was dissolved in trimethyl orthoformate dimethylformamide (2 mL, 3: 1), acetaldehyde (32 μL, 570 μM), and sodium cyanoborohydride (18 mg, 285 μM), and the resulting mixture was stirred at room temperature for 1 h. The residue after evaporation was passed through a silica column and the free base was eluted with ammonia-saturated methylene chloride-methanol (6: 1). The crude product obtained by evaporation of the eluates was purified by HPLC (C-18, 0.1% trifluoroacetic acid in methanol-water 35:65) to give 15.7 mg (42%) of the title product.
¹ H-NMR (400 MHz, CD ₃ OD): δ 7.80 (1H, s); 7.76 (1H, dd, J 2.4 and 9.9 Hz); 7.67 (1H, dd, J 4.1 and 9.0 Hz); 7.39 (1H, dd, J 4.1 and 8.7 Hz); 7.13 (1H, dt, J 2.3 and 9.0 Hz); 7.09-7.00 (2H, m); 6.73 (1H, s); 5.29 (1H, sym.m., J 7.5 Hz); 4,11-4,02 (1H, m); 3.61 (3H, s); 3.53-3.39 (1H, m); 3.25-3.12 (1H, m); 2.96-2.90 (2H, m); 2.65-2.43 (3H, m); 2.26-2.17 (1H, m); 2.07-1.98 (1H, m); 1.49-1.29 (6H, m).
APCI-MS m / z: 505.3 [MH +].

Example 110

4- [1- (3-bromopropyl) -5-fluoro-indol-3-yl] -5- (1-H-indol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one

A mixture of 4- [1- (3-hydroxypropyl) -5-fluoroindol-3-yl] -5- (1-H-indol-3-yl) -2,4-dihydro [1,2,4] triazole 3-one (0.230 g, 0.59 mmol), which was synthesized according to the procedure for Example 1, triphenylphosphine (0.168 g, 0.64 mmol) and tetrabromomethane (0.21 g, 0.66 mmol) in dry THF (15 ml) was added with triphenylphosphine (0.168 g, 0.64 mmol). The resulting mixture was stirred at ambient temperature. After 16 h, according to LCMS, still some starting material was present. Upon addition of additional tetrabromomethane (0.198g, 0.60mmol) and triphenylphosphine (0.158g, 0.60mmol), the solution was allowed to continue for an additional 20 hours at ambient temperature. Evaporation and silica gel chromatography (dichloromethane / methanol, gradient to 100/5) gave 0.165 g (57%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 11.20 (1H, s); 8.07 (1H, d); 7.81 (1H, s); 7.70 (1H, dd); 7.37 (1H, d); 7.18-7.08 (3H, m); 7.02 (1H, dd); 4.39 (2H, t); 3.45 (2H, t); 2.34 (2H, p).
APCI MS m / z: 456.1 [MH +].

Example 111

4- [1- (3-cyanopropyl) -5-fluoro-indol-3-yl] -5- (1-H-indol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one hydrochloride

To the product of Example 110 (0.052 g, 0.114 mmol) in THF (3.0 mL) was added a solution of potassium cyanide (0.040 g, 0.614 mmol) in a little water and the solution stirred at 50 ° C for 16 h. Evaporation and silica gel chromatography (dichloromethane / methanol, gradient to 100/5) gave 0.014 g (31%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 11:18 (1H, s); 8.07 (1H, d); 7.82 (1H, s); 7.70 (1H, dd); 7.37 (1H, d); 7.18-7.08 (3H, m); 7.01 (1H, dd); 6.67 (1H, dd); 4.33 (2H, t); 2.48 (2H, t); 2,12 (2H, p).
LCI-MS m / z: 401.2 [MH +].

Example 112

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-H-indol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one trifluoroacetate

To the product of Example 110 (0.053g, 0.116mmol) in THF (3.5ml) and water (0.35ml) was added sodium azide (0.014g, 0.215mmol) to give a solution which refluxed for 6 hours was heated. Evaporation followed by azeotropic distillation with a little THF gave a dry residue. This was dissolved along with triphenylphosphine (0.114 g, 0.435 mmol) in dry pyridine (5.0 mL). After stirring at ambient temperature for 10 min, 25% NH ₃ (aq) (1.0 ml) was added, after which the resulting mixture was stirred for a further 16 h. Evaporation followed by silica gel chromatography (dichloromethane / methanol / 25% NH ₃ (aq), gradient to 30/70/2) gave the title compound as the free base. This was dissolved in methanol along with trifluoroacetic acid (0.100 ml, 1.30 mmol). Evaporation followed by addition of water and lyophilization afforded 29 mg (50%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 11:18 (1H, s); 8,10 (1H, d); 7.83 (1H, s); 7.77 (3H, bs); 7.73 (1H, dd); 7.38 (1H, d); 7.25-6.99 (3H, m); 7.03 (1H, dd); 6.54 (1H, dd); 4.37 (2H, t); 2.80 (2H, m); 2.08 (2H, p).
ESI-MS m / z: 391.1 [MH +].

Example 113

4- [1- (3 - (- (4-methyl-1-piperazinyl)) - 5-fluoro-indol-3-yl] -5- (1-H-indol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one dihydrochloride

1-Methylpiperazine (0.068 g, 0.677 mmol) and the product from Example 110 (0.0615 g, 0.135 mmol) were refluxed in THF (5.0 mL) for 5 h. Evaporation and chromatography on silica (dichloromethane / methanol / 25% NH ₃ (aq), 100/10/1) gave 0.037 g (50%) of the title compound as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 11:27 (1H, s); 8.11 (1H, d); 7.84 (1H, s); 7.76 (1H, dd); 7.40 (1H, d); 7:17 (1H, t); 7.15-7.10 (2H, m); 7.03 (1H, dd); 6.62 (1H, dd); 4.39 (2H, m); 3.63-3.08 (9H, broad m); 2.81 (4H, bs); 2.22 (2H, wide m).
APCI MS m / z: 474.3 [MH +].

Example 114

4- [5-fluoro-1- (3-hydroxypropyl) indole-3-yl] -5- (1-isopropylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one

The title compound was synthesized in analogy to the synthesis of the product of Example 1.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 8,10 (1H, d); 7.82 (1H, s); 7.68 (1H, dd); 7.49 (1H, d); 7.21 (1H, t); 7.15 (1H, t); 7.09 (1H, dt); 6.94 (1H, dd); 6.56 (1H, s); 4.67 (1H, t); 4.57 (1H, p); 4.34 (2H, t); 3.41 (2H, q); 1.94 (2H, p); 1.01 (6H, d).
APCI-MS m / z: 434.1 [MH +].

Example 115

4- (1-methyl-1H-indol-3-yl) -5- (8-aminomethyl-6,7,8,9-tetrahydro-pyrido [1,2-a] indol-10-yl) -2,4- dihydro- [1,2,4] triazol-3-one hydrochloride

a) 8-Azidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indole-10-carboxylic acid hydrazide

Attention! The hydrazine azide salt by-produced in this synthesis is explosive and should not be isolated or concentrated! The product of Example 13a) (0.655 g, 2.218 mmol) in THF (10 mL) was added hydrazine hydrate (0.445 mL, 9.20 mmol). The mixture was stirred at ambient temperature for 16 hours and then partitioned between ethyl acetate (30 ml) and water (50 ml). The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were evaporated, yielding 0.640 g (99%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 8.65 (1H, s); 7.80 (1H, d); 7.40 (1H, d); 7.14 (1H, t); 7.11 (1H, t); 4.45 (2H, bs); 4.34 (1H, m); 3.90 (1H, dt); 3.52 (2H, d); 3.43 (1H, dd); 2.78 (1H, dd); 2.20-2.05 (2H, m); 1.80-1.70 (1H, m); 1.65 (1H, m).
APCI MS m / z: 285.1 [MH +].

b) 4- (1-methyl-1H-indol-3-yl) -5- (8-azidomethyl-6,7,8,9-tetrahydropyrido [1,2-a] indol-10-yl) -2, 4-dihydro- [1,2,4] triazol-3-one

1-Methyl-1H-indole-3-carbonyl azide (0.222 g, 1.109 mmol) was stirred in dry toluene (10 mL) at 130 ° C for 2 hours. Evaporation gave an oil (0.189 g). To this oil was added a solution of the product of a) (0.3158, 1.10 mmol) in dry DMF (10 ml) and the solution was stirred at room temperature for 15 min. Triethylamine (0.775 mL, 5.56 mmol) was added followed by trimethylsilyl triflate (1.000 mL, 5.53 mmol) and the resulting mixture heated to 130 ° C with stirring for 5 h. Then the solution was poured into water (150 ml). Filtration and silica gel chromatography (dichloromethane-methanol, gradient from 100/1 to 100/5) gave 0.121 g (25%) of the sub-title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.96 (1H, s); 7.46 (1H, s); 7.39 (1H, d); 7.29 (1H, d); 7.27 (1H, dd); 7, 16 (1H, d); 7.12 (1H, t); 7.01 (1H, t); 6.94 (1H, t); 6.87 (1H, t); 4.22 (1H, m); 3.80 (1H, dt); 3.70 (3H, s); 3.35 (1H, d); 3.09 (1H, m); 3.02 (1H, dd); 2.34 (1H, dd); 2.07 (1H, d); 1.91 (1H, m); 1.65 (1H, m).
APCI-MS m / z: 439.3 [MH +].

The product from b) (0.110 g, 0.251 mmol) and triphenylphosphine (0.328 g, 1.254 mmol) were stirred in pyridine (10 mL) at room temperature for one hour. Ammonia (aq, 25%) (3 ml) was added and the mixture was stirred for a further 16 h. Evaporation and silica gel chromatography (dichloromethane-methanol / 25% NH ₃ (aq), 90/10/2) gave 0.063 g of the title compound as the free base. This was dissolved in water (50 ml) along with 10 M HCl (1 ml). Lyophilization yielded 0.069 g (67%) of the title product as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.99 (1H, s); 8,16 (3H, bs); 7.57 (1H, s); 7.37 (1H, d); 7.28 (1H, d); 7.24 (1H, d); 7.19 (1H, d); 7,10 (1H, t); 7.00 (1H, t); 6.96 (1H, t); 6.86 (1H, t); 4.29-4.22 (1H, m); 3.79 (1H, dt); 3.71 (3H, s); 3.20 (2H, dd); 2.83 (2H, p); 2.21 (1H, d); 2.11 (1H, m); 1.70 (1H, m).
LSIMS ⁺ m / z: 413.3 [MH +].

The Products from Example 116 to Example 133 were used in analogy to Example 66 starting from the product of Example 45c) and the corresponding hydrazide produced.

Example 116

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (2-quinolinyl) -2,4-dihydro- [1,2,4] triazol-3-one dihydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.47 (1H, s); 8.41 (1H, d); 8,12 (3H, bs); 7.96 (1H, dd); 7.93 (1H, t); 7.81 (1H, s); 7.68 (1H, dd); 7.65 (1H, t); 7.56 (1H, t); 7.23 (1H, d); 7.04 (1H, dt); 6.99 (1H, dd); 4.38 (2H, t); 2.78 (2H, h); 2.09 (2H, p). LSI-MS m / z: 403.1 [MH +].

Example 117

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (2-naphthyl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.24 (1H, s); 8.04 (3H, bs); 7.98 (1H, s); 7.87-7.83 (3H, m); 7.73-7.68 (2H, m); 7.55-7.48 (3H, m); 7.10-7.02 (2H, m); 4.36 (2H, t); 2.74 (2H, h); 2.06 (2H, p). LSI-MS m / z: 402.1 [MH +].

Example 118

4- [1- (3-aminopropyl) 5-fluoro-indol-3-yl] -5-phenyl-2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.15 (1H, bs); 8.02 (3H, bs); 7.76 (1H, s); 7.68 (1H, dd); 7.40-7.28 (4H, m); 7.09 (1H, dt); 7.01 (1H, dd); 4.34 (2H, t); 2.70 (2H, m); 2.04 (2H, p). LSI-MS m / z: 352.0 [MH +].

Example 119

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (4-biphenyl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.18 (1H, bs); 8.11 (3H, bs); 7.83 (1H, s); 7.71 (1H, dd); 7.65-7.62 (4H, m); 7.50 (1H, s); 7.49 (1H, d); 7.43 (1H, t); 7.35 (1H, t); 7.13-7.05 (2H, m); 4.37 (2H, t); 2.74 (2H, m); 2.06 (2H, 9). LSI-MS m / z: 428.1 [MH +].

Example 120

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (4-phenoxyphenyl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.11 (1H, s); 7.94 (3H, bs); 7.79 (1H, s); 7.68 (1H, dd); 7.41-7.36 (4H, m); 7,16 (1H, t); 7,10 (1H, t); 6.99 (3H, d); 6.89 (2H, d); 4.35 (2H, t); 2.73 (2H, m); 2.04 (2H, p). ESI-MS m / z: 444.1 [MH +].

Example 121

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-ethoxyphenyl-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 12.15 (1H, s); 7.80 (2H, bs); 7.72 (1H, s); 7.66 (1H, dd); 7:18 (1H, t); 7.11 (1H, dt); 7.06 (1H, dd); 6.95-6.87 (3H, m); 4.31 (2H, t); 3.73 (2H, q); 2.76 (2H, t); 2.02 (2H, p); 1.13 (3H, t). APCI-MS m / z: 396.1 [MH +].

Example 122

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (4-phenyl-1-methylpyrrole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.82 (1H, s); 7.77 (3H, bs); 7.46 (1H, dd); 7.21-7.17 (2H, m); 7.08 (1H, tt); 7.02-6.94 (4H, m); 6.88 (1H, s); 6.83 (1H, d); 6.73 (1H, dd); 4,10 (2H, t); 3.56 (3H, s); 2.70 (2H, m); 1.90 (2H, p). APCI-MS m / z: 431.2 [MH +].

Example 123

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-ethyl-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 7.84 (1H, s); 7.77 (1H, s); 7.75 (2H, bs); 7.72 (1H, dd); 7.33 (1H, d); 7.13 (1H, dt); 7.08 (1H, dd); 7.03 (1H, dd); 6, 62 (1H, s); 4, 45 (2H, t); 3, 54 (3H, s); 2, 77 (2H, m); 2, 66 (2H, q); 2, 06 (2H, p); 1, 17 (3H, t).

Example 124

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-chloro-1-methylindole-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.96 (1H, s); 8.08 (1H, d); 7.82 (1H, s); 7.80 (2H, bs); 7.73 (1H, dd); 7.50 (1H, d); 7.26 (1H, dd); 7.14 (1H, dt); 7.05 (1H, dd); 6.69 (1H, s); 4.37 (2H, t); 3.58 (3H, s); 2.80 (2H, bs); 2.09 (2H, p). APCI-MS m / z: 439.1 [MH +].

Example 125

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (5-methoxy-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.88 (1H, s); 7.77 (1H, s); 7.74 (2H, bs); 7.72 (1H, dd); 7.48 (1H, d); 7.34 (1H, d); 7.14 (1H, dt); 7.06 (1H, dd); 6.86 (1H, dd); 6.63 (1H, s); 4.35 (2H, t); 3.68 (3H, s); 3.54 (3H, s); 2.77 (2H, m); 2.06 (2H, p). APCI-MS m / z: 435.3 [MH +].

Example 126

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1,2-dimethylindole-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.97 (1H, s); 7.66 (2H, bs); 7.55 (1H, s); 7.47 (1H, dd); 7.32 (1H, d); 7.22 (1H, d); 7.02-6.93 (2H, m); 6.90 (1H, dd); 6.84 (1H, dt); 4,15 (2H, t); 3.59 (3H, s); 2.57 (2H, m); 2.28 (3H, s); 1.85 (2H, p).

Example 127

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (6-methoxy-1-methylindol-3-yl) -2,4-dihydro- [1,2,4] triazole -3-one trifluoroacetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.87 (1H, s); 7.95 (1H, d); 7.81 (1H, s); 7.77 (2H, bs); 7.73 (1H, dd); 7.13 (1H, dt); 7.02 (1H, dd); 6.96 (1H, dd); 6.79 (1H, dd); 6.47 (1H, s); 4.37 (2H, t); 3.79 (3H, s); 3.51 (3H, s); 2.80 (2H, m); 2.09 (2H, p).

Example 128

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1,5-dimethylindole-3-yl) -2,4-dihydro- [1,2,4] triazol-3 -one hydrochloride

• ¹ H-NMR (400 MHz, CD ₃ OD): δ 7.85 (1H, bs); 7.65 (1H, dd); 7.62 (1H, s); 7.27 (1H, d); 7.15-7.10 (2H, m); 7.04 (1H, dd); 6.67 (1H, s); 4.44 (2H, t); 3.78-3.75 (2H, m); 3.57 (3H, s); 2.95 (2H, t); 2.43 (3H, s); 2.27-2.20 (2H, m).

Example 129

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-propylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 8.07 (1H, d); 7.98-7.71 (4H, m); 7.47 (1H, d); 7.21 (1H, t); 7.16-7.08 (2H, m); 6.93 (1H, d); 6.58 (1H, s); 4.37 (2H, m); 3.89 (2H, t); 2.81 (2H, hex); 2.09 (2H, m); 1.41 (2H, hex); 0.42 (3H, t). APCI-MS m / z: 433.1 [MH +].

Example 130

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- [1- (2-fluoroethyl) indol-3-yl] -2,4-dihydro- [1,2,4 ] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.94 (1H, s); 8,10 (1H, d); 8.03 (2H, s); 7.84 (1H, s); 7.74 (1H, dd); 7.51 (1H, d); 7.23 (1H, t); 7,16 (1H, t); 7.11 (1H, dt); 6.98 (1H, dd); 6.68 (1H, s); 4.50 (1H, t); 4.40-4.37 (3H, m); 4.33 (1H, t); 4.26 (1H, t); 2.78 (2H, m); 2,10 (2H, p). LSI-MS m / z: 437.2 [MH +].

Example 131

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-ethylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one hydrochloride

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.91 (1H, s); 8.07 (1H, d); 7.86 (2H, bs); 7.84 (1H, s); 7.73 (1H, dd); 7.48 (1H, d); 7.22 (1H, t); 7, 16-7, 10 (2H, m); 6.96 (1H, dd); 6.64 (1H, s); 4.38 (2H, t); 3.97 (2H, q); 2.80 (2H, m); 2.08 (2H, m); 1.02 (3H, t). LSI-MS m / z: 419.2 [MH +].

Example 132

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- [1- (2-hydroxyethyl) indol-3-yl] -2,4-dihydro- [1,2,4 ] triazol-3-one hydrochloride

• APCI-MS m / z: 435.3 [MH +].

Example 133

4- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -5- (1-benzylindol-3-yl) -2,4-dihydro- [1,2,4] triazol-3-one -acetate

• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 11.94 (1H, s); 8.09 (1H, d); 7.96 (2H, bs); 7.86 (1H, s); 7.73 (1H, dd); 7.47 (1H, d); 7.21-7.10 (6H, m); 6.90 (1H, dd); 6.81-6.78 (2H, m); 6.71 (1H, s); 5.16 (2H, s); 4.37 (2H, t); 2.79 (2H, hex); 2.08 (2H, p). APCI-MS m / z: 481.1 [MH +].

The products listed in Table 1 according to Examples 134 to 182 were prepared in analogy to Example 66 starting from the product of Example 45c) and the corresponding hydrazide. Table 1

Table 2

The listed in Table 2 Products according to example 183 to Example 239 were starting in analogy to Example 66 of 3-azidocarbonyl-1- (3-dimethylaminopropyl) -5-fluoro-1H-indole and the corresponding hydrazide produced.

Example 240

5- [1- (3-aminopropyl) -5-fluoro-indol-3-yl] -4- (1-naphthyl) -2,4-dihydro-1,2,4-triazole-3-thione hydrochloride

This compound was synthesized in analogy to the above examples but starting from 1-naphthylisothiocyanate.
ESI-MS m / z: 418.1 [MH +].

Abbreviations

• DMF = N, N-dimethylformamide
• MS = mass spectroscopy
• NMR = nuclear magnetic resonance
• THF = tetrahydrofuran
• Triflate = trifluoromethanesulfonate
• TBS = tert-butyldimethylsilyl
• TFA = trifluoroacetic acid
• dba = dibenzylideneacetone

Claims (16)

Compound of the formula (I):

wherein one of Ar ₁ and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or in the event that one of Ar ₁ and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl, may also stand for S and R is H, OH, NH ₂ or C _1-6 alkyl (optionally self-substituted by amino or hydroxy); Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinozilin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl and bicyclic heteroaryl and tricyclic heteroaryl are respectively selected from heteroaryl; Aryl is phenyl or naphthyl; the optional substituent or the optional substituents on the heteroaryl and aryl groups from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 -alkyl (optionally substituted by halogen, Hydroxy, cyano, C _1-4 alkoxy (optionally substituted by NH ₂ , CO ₂ (C _1-4 alkyl)), NR ^a R ^b , SC (= NH) NH ₂ , C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino)), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (given optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another are hydrogen or C _1-4 -alkyl (optionally themselves substituted by hydroxyl, phenyl, CO ₂ H or CO ₂ (C _1-4 -alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^q , R ^h , R ⁱ , R ^j , R ^k and R ¹ independently represent hydrogen, C _1-4 alkyl or phenyl-C _1-4 alkyl or R ^k and R ^l together form a heterocyclic ring; or a salt or solvate thereof or a solvate of a salt thereof; with the proviso that in the event that X is O, R is hydrogen and one of Ar ₁ and Ar _{2 is} phenyl or phenyl optionally substituted by halogen or C _1-4 alkyl, the other is not 3,4-methylenedioxy phenyl, unsubstituted benzthiazol-2-yl, a phthalimide or 1,8-naphthalimide. A compound according to claim 1, wherein bicyclic heteroaryl and heteroaryl independently each other for substituted Indolyl stand. A compound according to claim 1, wherein X is oxygen stands. A compound according to any one of the preceding claims, wherein which is a hydrochloride, hydrobromide or acetate salt. Compound of the formula (II) or (III):

wherein: Ar ₁ and Ar _{2 are} optionally substituted heteroaryl or optionally substituted aryl; R is hydrogen or C _1-3 alkyl; X is O or, in the case where Ar ₁ or Ar _{2 is} optionally substituted heteroaryl, may also stand for S; Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinozilin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl stands; Aryl is phenyl or naphthyl; the optional substituent or the optional substituents on the heteroaryl and aryl groups from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 -alkyl (optionally substituted by halogen, Hydroxy, cyano, C _1-4 alkoxy (optionally substituted by NH ₂ , CO ₂ (C _1-4 alkyl)), NR ^a R ^b , SC (= NH) NH ₂ , C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (itself optionally substituted by amino))), C ₅ - ₆ cycloalkyl (optionally substituted by ⁿ hydroxy, NR ^m R or alkyl (itself optionally substituted by NR ^o R ^p)), C _5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (gege optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another are hydrogen or C _1-4 -alkyl (optionally themselves substituted by hydroxyl, phenyl, CO ₂ H or CO ₂ (C _1-4 -alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , R ^j , R ^k and R ^l independently represent hydrogen, C _1-4 alkyl or phenyl-C _1-4 alkyl or R ^k and R ^l together form a heterocyclic ring; R 1 and R 2 each independently represent H, C _1-6 alkyl, halogen, C _1-3 alkoxy, benzyloxy, hydroxy, cyano, fluoro-substituted C _1-3 alkyl, carboxy or carbo-C _1-3 alkoxy ; R 3 is H, C _1-6 -alkyl, benzyl, C _1-3 -alkoxy-substituted benzyl, hydroxy-C _1-6 -alkyl, hydroxy-C _3-7 -cycloalkyl, nitrilo-C _1-6 -alkyl, azido C _1-6 alkyl, amino C _1-6 alkyl, amino C _3-7 cycloalkyl, aminomethyl C _3-7 cycloalkyl, amino C _5-7 cycloalkenyl, (mono- or di-C _1-6- alkylamino-C _1-6 -alkyl, benzylamino-C _1-6 -alkyl, (mono- or di-C _1-6 -alkylamino-C _3-7 -cycloalkyl, (mono- or di- C _1-6 alkyl) aminomethyl C _3-7 cycloalkyl, (amino C _1-3 alkylphenyl) C _1-3 alkyl, amino C _1-3 alkylphenyl, guanidino C _1-6 alkyl, amidinoC _1-6 alkyl, amidinothioC _1-6 alkyl, [N, N-diC _1-6 alkyl] amidinoC _1-6 alkyl, amidinoC _1-3 alkylphenyl, [N, N-mono- or di-C _1-6 -alkyl] amidino-C _1-3 -alkylphenyl, (N -benzyl) amidino-C _1-3 -alkylphenyl, (4-morpholinyl) imino-C _1-3 -alkylphenyl, methyl benzimidate C _1-3 alkyl, hydroxyC _1-3 alkylaminoC _1-6 alkyl, carboxyC _1-3 alkylaminoC _1-6 alkyl, carboxymethyl 1-C _1-3 alkylaminoC _1-6 alkyl, aminoC _1-3 alkyloxyC _2-6 alkyl, formamidoC _1-6 alkyl, (N, N-dimethyl) imidoformamide C _{1 -6-} alkyl or a group of the formula - (CH ₂ ) _n -Het, wherein n is an integer of 0-6 and Het is an optionally substituted 5- or 6-membered heterocyclic group, and R4 is H or C _1-3 alkyl or together with R3 forms a fused ring, which may be replaced by Hydroxy C _1-3 alkyl or amino C _1-3 alkyl; or a salt or solvate thereof or a solvate of a like salt. Compound of the formula (XV):

wherein R, R 1, R _2, R 3 and R _{4 are} as defined in claim 5 and Ar _{2 is} optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl; bicyclic heteroaryl and tricyclic heteroaryl as quinolinyl, isoquinolinyl, xanthen-9-yl, quinozilin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b ] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or indolyl; bicyclic heteroaryl and tricyclic heteroaryl are optionally substituted by halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 alkyl (optionally substituted by halogen, hydroxy, cyano, C _1-4 alkoxy (optionally substituted by NH _2, CO ₂ (C _1-4 alkyl), ^b), NR ^a R, SC (= NH) NH _2, C (= NH) NR ^c R ^d, N = C (R ^e) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C 1-4 alkyl or phenyl-C 1-4 alkyl), phenyl (optionally substituted by C _{1 -4-} alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally substituted by amino)) ), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (optionally itself substituted by NR ^s R ^t )), Hete rocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl), phenoxy and amino (optionally substituted by C _{1 4-} alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another represent hydrogen or C _{1-4 -alkyl} ( optionally themselves substituted by hydroxy, phenyl, CO ₂ H or CO ₂ (C _1-4 alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , R ^j , R ^k and R ¹ independently of one another are hydrogen, C _1-4 -alkyl or phenyl-C _1-4 -alkyl or R ^k and R ¹ together form a heterocyclic ring. Compound of the formula (IV):

wherein R 1 to R 4 are as defined in claim 5, R 5 is H, C _1-6 alkyl, benzyl, hydroxyC _1-6 alkyl or aminoC _1-6 alkyl and R 6 and R 7 are independently from each other H, C _1-3 alkyl, halogen, cyano, fluoro-substituted C _1-3 alkyl, C _1-3 alkoxy, benzyloxy, hydroxy, cyano, carboxy or carbo-C _1-3 alkoxy; or a salt or solvate thereof or a solvate of such a salt. Pharmaceutically acceptable salt or hydrate of a A compound according to any one of the claims 1 to 7 or a hydrate of such a salt. Pharmaceutical formulation containing a compound according to one of the claims 1 to 7 or a salt or hydrate according to claim 8 as an active ingredient and a pharmaceutically acceptable excipient, a pharmaceutical safe diluent and / or a pharmaceutically acceptable carrier therefor. A compound according to any one of claims 1 to 7 or salt or A hydrate according to claim 8 for use in medical therapy. Use of a compound of the formula (I):

wherein one of the radicals Ar ₁ and A _{r 2} is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or S and R is H, OH, NH 2 or C _1-6 alkyl (optionally self-substituted by amino or hydroxy); Heteroaryl for pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinozilin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido [3,4-b] indolyl, 1H-pyrrolo [2,3-b] pyridinyl, 6,7,8,9-tetrahydropyrido [1,2-a] indolyl, 2,3-dihydro-1H-pyrrolo [1,2-a] indolyl or Indolyl and bicyclic heteroaryl and tricyclic heteroaryl are respectively selected from heteroaryl; Aryl is phenyl or naphthyl; the optional substituent or the optional substituents on the heteroaryl and aryl groups from the group consisting of halogen, cyano, nitro, hydroxy, CO ₂ (C _1-4 alkyl), C _1-8 -alkyl (optionally substituted by halogen, Hydroxy, cyano, C _1-4 alkoxy (optionally substituted by NH ₂ , CO ₂ (C _1-4 alkyl)), NR ^a R ^b , SC (= NH) NH ₂ , C (= NH) NR ^c R ^d , N = C (R ^e ) NR ^f R ^g , N (R ^h ) C (= O) R ⁱ , NHC (= NH) NH ₂ , heterocyclyl (optionally substituted by C _1-4 alkyl or phenyl-C _1-4 alkyl), phenyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino), C (= NH) OR ^j , C (= NH) NR ^k R ^l ), pyridinyl (optionally substituted by C _1-4 alkyl (optionally self-substituted by amino)), C _5-6 cycloalkyl (optionally substituted by hydroxy, NR ^m R ⁿ or alkyl (optionally self-substituted by NR ^o R ^p )), C _5-6 -Cycloalkenyl (optionally substituted by NR ^q R ^r or alkyl (given optionally substituted by NR ^s R ^t )), heterocyclyl (optionally substituted by C _1-4 alkyl or C _1-4 haloalkyl), phenyl (optionally substituted by halogen), C _1-6 alkoxy (optionally substituted by phenyl ), Phenoxy and amino (optionally substituted by C _1-4 alkyl), where R ^a , R ^b , R ^m , R ⁿ , R ^o , R ^p , R ^q , R ^r , R ^s and R ^t independently of one another are hydrogen or C _1-4 -alkyl (optionally themselves substituted by hydroxyl, phenyl, CO ₂ H or CO ₂ (C _1-4 -alkyl)) and R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , R ^j , R ^k and R ^l independently represent hydrogen, C _1-4 alkyl or phenyl-C _1-4 alkyl or R ^k and R ^l together form a heterocyclic ring; or a salt, solvate or hydrate thereof or a solvate or hydrate of a salt thereof in the manufacture of a medicament for use in inflammatory diseases, immunological diseases, bronchopulmonary diseases, cardiovascular diseases, oncological diseases or CNS diseases. A process for the preparation of a compound of formula (I) according to claim 1, wherein: i. for a compound in which R is C _1-3 -alkyl (optionally substituted by amino or hydroxy), a compound of formula (I) in which R is hydrogen, with the corresponding (optionally substituted by amino or hydroxy) C _1-3 alkylating agent alkylated; ii. for a compound of the formula (I) in which R is hydrogen, a compound of the formula (VI)

condensed intramolecularly; iii. for a compound of formula (I) in which Ar ₁ , Ar ₂ and / or R bear one or more functional groups which may be sensitive to or interfere with the reaction conditions in the processes in (a) or (b) corresponding starting material, in which the functional group or the functional groups are suitably protected or are used, and then deprotected by the method according to (a) or (b). A process for the preparation of a compound of formula (II) or (III) according to claim 5, wherein: i. in the case where R 3 is an alkyl group carrying an amino group, a compound of the formula (IX) or (X):

reduced; ii. in the event that R3 is an alkyl group carrying a thioamidino or a monoalkyl, dialkyl or trialkylamino group, reacting a compound of the formula (XI) or (XII) with thiourea or a suitable monoalkyl, dialkyl or trialkylamine

wherein R, R _1, R _2, R ₄ , Ar ₁ and Ar ₂ are as defined in claim 5, R _{3 11 is} an alkyl group and LG is a leaving group. Process for the preparation of a compound of the formula (II) or (III) according to claim 5, wherein R 3 is an amidino or guanidino group carrying alkyl group, in which: i) a connection of the formula (II) or (III) wherein R 3 represents a nitrile group-bearing one Alkyl group is, with hydrogen chloride in ethanol and then with Reacting ammonia in methanol; or ii) a compound of Formula (II) or (III) wherein R3 is a primary amino group carrying alkyl group, in refluxing ethanol in the presence a base with 3,5-dimethylpyrazole-1-carboxamidiniumnitrat. Process for the preparation of a compound of the formula (II) or (III) according to claim 5, wherein R 3 is an N-substituted one or N, N-disubstituted Amidino group bearing alkyl or phenylalkyl group, in which a compound of the formula (II) or (III) in which R 3 is a Nitrile group bearing alkyl or phenylalkyl group, with hydrogen chloride in methanol and then with the corresponding amine in methanol. Intermediate of formulas (VI), (IX), (X), (XI), (XII), (XIII) or (XIV):

wherein Ar ₁ and Ar ₂ are as defined in claim 1; R, R1, R2 and R4 are as defined in claim 5; R3 is an alkyl group bearing a nitrile group or a primary amino group; R3 _{11 is} an alkyl group and LG is a leaving group.